Prodrugs of fencamfamine

ABSTRACT

Disclosed herein are pharmaceutical compositions with fencamfamine or fencamfamine related prodrug derivatives. The pharmaceutical compositions are for targeted therapeutic applications including, but not limited to, treating cancer-related fatigue, apathy in Alzheimer&#39;s Disease, major depression, and attention deficit-hyperactivity disorder. Also disclosed are methods of synthesizing the pharmaceutical compositions with fencamfamine or fencamfamine related prodrug derivatives.

This application is the 371 of international application numberPCT/US2016/051534, which claims priority to U.S. Provisional ApplicationSer. 62/219,052, filed Sep. 15, 2015, Ser. No. 62/298,267, filed Feb.22, 2016, and Ser. No. 62/308,078, filed Mar. 14, 2016, each of which isincorporated by reference.

FIELD

The present disclosure relates to organic compounds, for example,prodrug derivatives of N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine orany of its stereoisomers. More particularly disclosed herein arepharmaceutical prodrug compositions ofN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, and methods ofsynthesizing the same.

BACKGROUND

Fencamfamine (Glucoenergan, Reactivan) is a stimulant which wasdeveloped in the 1960s as a treatment for reduced performance andrehabilitation from prolonged and debilitating diseases; treatment ofdepressive day-time fatigue, lack of concentration and lethargy (Brazil,European countries, South Africa, etc.).

SUMMARY

Some embodiments disclosed herein include compound of Formula (I)including forms such as stereoisomers, free forms, pharmaceuticallyacceptable salts or esters thereof, solvates, or combinations of suchforms, wherein Y is defined herein.

In some embodiments, a fencamfamine prodrug is provided. Thefencamfamine prodrug comprises fencamfamine, and a Y moiety (definedbelow) conjugated to the fencamfamine. In some embodiments, the Y moietyis selected from the group consisting of —C(O)X and (A)_(n); wherein Xis selected from the group consisting of —OR¹, —NHR¹, —NR¹R⁵,—O(CR²R⁶)OR³, —O(CR²R⁶)SR³, O(CR²R⁶)NR³ and R⁴; wherein R¹ isindependently selected from optionally substituted C₁₋₁₆ alkyl,optionally substituted aryl, and optionally substituted cycloalkyl;wherein R², R⁵, and R⁶ are independently selected from hydrogen,optionally substituted C₁₋₆ alkyl; wherein R³ is independently selectedfrom optionally substituted C₁₋₂₆ alkanoyl; optionally substituted C₁₋₂₆alkenoyl, optionally substituted C₁₋₂₆ alkynoyl; optionally substitutedcycloalkanoyl; wherein R⁴ is independently selected from optionallysubstituted C₁₋₂₆ alkyl; optionally substituted C₁₋₂₆ alkenyl,optionally substituted C₁₋₂₆ alkynyl; optionally substituted cycloalkyl;and wherein (A)_(n) is a peptide unit formed with amino acid unitswherein n is independently 1, 2, 3, or 4. In some embodiments, R¹ isselected from the group consisting of Me, Et, ^(t)Bu,5-isopropyl-2-methylphenyl, and 2-isopropyl-5-methylphenyl. In someembodiments, R² and R⁶ are independently selected from the groupconsisting of H and Me. In some embodiments, R² and R⁶ are independentlyselected from the group consisting of H and Me, R³ is independentlyselected from optionally substituted C₁₋₂₆ alkanoyl. In someembodiments, R² and R⁶ are independently selected from the groupconsisting of H and Me, R³ is independently selected from optionallysubstituted C₁₋₂₆ alkanoyl, and R³ is from C₁₂ to C₁₈ in chain length.In some embodiments, R³ is selected from the group consisting of acetyl,pivaloyl, butyryl, capryloyl, decanoyl, lauroyl, and stearoyl. In someembodiments, X is —O(CHR²)OR³. In some embodiments, when X is—O(CHR²)OR³, R² is independently selected from hydrogen, optionallysubstituted C₁₋₆ alkyl. In some embodiments, R⁴ is —(CO)CH₂CH₂COOH. Insome embodiments, (A)_(n) is selected from the group consisting of Val,Lys, Gly, Gly-Gly, Val-Val, Gly-Ala, Phe, Phe-Phe, Ala-Gly, and Lys-Lys.In some embodiments, R³ is selected from the group consisting of theacyl group of a fatty acid; C-12 fatty acid (dodecanoyl); C-16 fattyacid; C-18 fatty acid (octadecanoyl); C-20 fatty acid; C-22 fatty acid;C-24 fatty acid; and C-26 fatty acid.

In some embodiments, Y is selected from the group consisting ofacyloxymethoxycarbonyl (R³C(O)OCH₂OCO—); 1-acyloxyethoxycarbonyl(R³C(O)OCH(Me)OCO—). X is —O(CR²R⁶)OR³; R² and R⁶ are independentlyselected from hydrogen, optionally substituted C₁₋₆ alkyl; and R³ isindependently selected from optionally substituted C₁₋₂₆ alkanoyl oroptionally substituted C₁₋₂₆ alkenoyl. acyloxymethoxycarbonyl,(R³C(O)OCH₂OCO—). In some embodiments, Y can be any addition to thefencamfamine structure, as depicted in any one of formula providedherein.

In some embodiments, a fencamfamine prodrug is provided. Thefencamfamine prodrug comprises fencamfamine, a linker conjugated to thefencamfamine, and a fatty acid or at least one amino acid conjugated tothe linker.

In some embodiments, a method for treating cancer-related fatigue isprovided. Other targeted therapeutic applications include apathy inAlzheimer's Disease, major depression, attention deficit-hyperactivitydisorder, etc. The method comprises administering to the subject aneffective amount of any one or more of the compounds provided herein toa subject in need thereof.

In some embodiments, a prodrug composition comprising at least oneconjugate of N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine or any of itsstereoisomers is provided. The conjugate is of the following formula(I):

wherein Y is selected from the group consisting of —C(O)X and (A)_(n);wherein: X is selected from the group consisting of —OR¹, —NHR¹, —NR¹R⁵—O(CR²R⁶)OR³, —O(CR²R⁶)SR³, O(CR²R⁶)NR³ and R⁴, wherein R¹ isindependently selected from optionally substituted C₁₋₁₆ alkyl,optionally substituted aryl, and optionally substituted cycloalkyl.Wherein R², R⁵, and R⁶ are independently selected from hydrogen,optionally substituted C₁₋₆ alkyl; wherein R³ is independently selectedfrom optionally substituted C₁₋₂₆ alkanoyl; optionally substituted C₁₋₂₆alkenoyl, optionally substituted C₁₋₂₆ alkynoyl; optionally substitutedcycloalkanoyl; wherein R⁴ is independently selected from optionallysubstituted C₁₋₂₆ alkyl; optionally substituted C₁₋₂₆ alkenyl,optionally substituted C₁₋₂₆ alkynyl; optionally substituted cycloalkyl;and wherein (A)_(n) is a peptide unit formed with amino acid unitswherein n is independently 1, 2, 3, or 4.

Some embodiments disclosed herein relate to methods for treatingcancer-related fatigue. In a mammal, comprising administering to themammal an effective amount of one or more compounds of Formula (I)including forms such as stereoisomers, free forms, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includesone or more compounds of Formula (I) including forms such asstereoisomers, free forms, or a pharmaceutically acceptable saltthereof. Other embodiments described herein relate to using one or morecompounds of Formula (I) including forms such as stereoisomers, freeforms, or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for treatment of cancer-related fatigue. These and otherembodiments are described in greater detail below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a set of comparative data of single dose oral andintravenous PIK Study of PRX-P4-003.

FIG. 2 is a graph depicting oral and IV pharmacokinetics for PRX-P4-003in male Sprague Dawley rats.

FIG. 3 depicts the results of the comparative data regarding IV PKstudies of PRX-P4-003 (2 and 10 mg/kg b.w.) PRX-002(−) isomer (2 mg/kgb.w.).

FIG. 4 is a graph comparing the oral PK study of PRX-P4-003 toPRX-002(−) isomer, in terms of the amount of resulting PRX-P4-003 orPRX-P4-002(−) isomer present in the plasma.

FIGS. 5A and 5B show comparative Data: Single Dose Oral and IntravenousPK Study of PRX-P5-006.

FIG. 6A is a graph depicting a comparison of oral and IVpharmacokinetics of PRX-P5-006 in Male Sprague Dawley rats.

FIG. 6B shows an enlarged view of the IV pharmacokinetics for the amountof resulting active in the plasma depicted in FIG. 6A.

FIGS. 7A and 7B show graph depicting the IV pharmacokinetics forPRX-P5-011 in male Sprague Dawley rats.

FIG. 8A is a graph depicting the IV pharmacokinetics of PRX-P6-011 inmale Sprague Dawley rats.

FIG. 8B is a more closely visualized graph (from 8A) consisting ofPRX-P6-011, PRX-002 (+) [compared to the level of PRX-002 (−) afterdirect administration].

FIGS. 9A, 9B, and 9C show graph of PRX-002 (+) administered to the ratsat a dose of 5 mg kg orally or 2 mg/kg intravenously.

FIGS. 10A, 10B, and 10C show graph of PRX-002 (−) administered to therats at a dose of 5 mg kg orally or 2 mg/kg intravenously.

FIGS. 11A and 11B: Total traveling distance (cm, FIG. 11A) and duration(sec, FIG. 11B) of locomotor activity of every 15 min. Data wereexpressed as Mean±S.E.M. and analyzed with Repeated measures ANOVAfollowed by Bonferroni test compared to vehicle group. * P<0.05, **P<0.01, *** P<0.001: vs. Veh group.

FIGS. 12A and 12B: Total traveling distance (cm, FIG. 12A) and duration(sec, FIG. 12B) of locomotor activity of every 15 min. Data wereexpressed as Mean±S.E.M. and analyzed with Repeated measures ANOVAfollowed by Bonferroni test compared to vehicle group. * P<0.05, **P<0.01, *** P<0.001: vs. Veh group.

DETAILED DESCRIPTION

The following description and examples illustrate various embodiments ofthe present disclosure in detail. Those of skill in the art willrecognize that there are numerous variations and modifications of thisdisclosure that are encompassed by its scope. Accordingly, thedescription of the disclosed embodiment should not be deemed to limitthe scope of the present disclosure.

Cancer-related fatigue (CRF) is a widespread adverse symptom related tocancer and cancer therapy. In a recent study, cancer patients reportedthat fatigue is the most distressing symptom associated with theircancer and cancer treatment (Richardson et al, 1995). CRF is amulticausal, multidimensional, and complex disturbance and hence isdifficult to describe for patients, their families and even for healthcare providers (Portenoy et al, 1999). CRF can be best defined as anunusual and persistent sense of tiredness that can occur with cancer andcancer therapy (Atkinson et al, 2000). CRF may affect both physical andmental capacity and is unrelieved by rest. It is more severe, moreenergy draining, longer lasting and more unrelenting than other forms offatigue (Glaus et al, 1996). CRF interferes with usual functioning andhas a devastating effect on almost all aspects of patients' lives. Ithas a pervasive effect on motivation. Additionally, attending andcompleting a task becomes difficult. The most unusual characteristic ofCRF is that it is unrelieved by rest or additional sleep (Holly, 2000).Most of the current pharmacological and non-pharmacological treatmentsoffered by health care professionals are based on anecdotal evidence.

As noted above, fencamfamine (Glucoenergan, Reactivan) is a stimulantwhich was developed by E Merck in the 1960s. Until recently there havebeen reports that fencamfamine was still rarely used for treatingdepressive day-time fatigue, lack of concentration and lethargy,particularly in individuals who have chronic medical conditions,although its favorable safety profile makes it the most suitable drug insome cases. Fencamfamine increases drive and mental alertness and anelevation of mood and a general feeling of well-being.

Fencamfamine acts as an indirect dopamine agonist. The drug seems toinhibit the dopamine transporter (DAT) that removes dopamine from thesynapses. This inhibition of DAT blocks the reuptake of dopamine andnorepinephrine into the presynaptic neuron, increasing the amount ofdopamine in the synapse. Also unlike amphetamines, fencamfamine does notappear to inhibit the action of monoamine oxidase enzymes and so issomewhat safer.

Due to its efficacy and extensive use in treating fatigue-relatedconditions fencamfamine could provide a pharmacological approach totreat CRF. In some embodiments provided herein, prodrug compositions offencamfamine can provide a treatment for CRF while avoiding and/orreducing the drug-abuse profile but still providing the ability to dosevia routine administration routes, e.g. oral.

In some embodiments, prodrug versions of fencamfamine allow for greateramounts of fencamfamine to be present in the plasma of the subject. Insome embodiments, it allows for greater amounts of fencamfamine to bepresent in the plasma of the subject from oral administration of theprodrug to the subject.

In some embodiments, prodrug versions of fencamfamine allow for aparticular isomer of fencamfamine to be provided to the subject.

The present disclosure provides derivatives and/or combinations thereofof fencamfamine (or N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine) inprodrug form (including particular isomers thereof). In someembodiments, the fencamfamine is conjugated to at least one group Y asdefined below (which may or may not be cleavable) such as but notlimited to amides, acyloxyalkoxycarbonyl moieties or derivativesthereof, which are novel prodrug compositions and/or conjugates ofN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine. In some embodiments, ablocker and linker work together to form the prodrug, and thus, there isno necessary distinction between the two in terms of functional aspectsfor each embodiment. Thus, in some embodiments, the designation oflinker and blocking moiety is a short hand to describe structuralaspects, rather than functional aspects. In some embodiments, the groupY forms the prodrug.

In some embodiments, the prodrugs provided herein allow for a reducedrisk of abuse or addiction by a user or patient. In some embodiments,this can be achieved by providing a release profile such that there isonly an adequate amount of the active compound if the prodrug is takenorally. However, when the prodrug is taken by IV, it is not broken downinto its active form in a substantial amount in the subject. With thisrelease aspect, a subject's ability to receive, via IV, a large amountof the active form of the molecule is reduced (as taking a large amountof the prodrug via IV does not necessarily result in an increase of theactive in the plasma levels, for various embodiments). Some exemplaryembodiments of such prodrugs include PRX-P5-006 and PRX-P4-003 (whichinclude a (−) isomer of fencamfamine). In some embodiments, thecomposition is one in which a fencamfamine is bonded to an adequatelysized fatty acid (such as C-12 (dodecanoic acid) or C-18 (octadecanoicacid)). In some embodiments, linkage is via an appropriate Y moiety,such, as acyloxymethoxycarbonyl (R³C(O)OCH₂OCO—) or1-acyloxyethoxycarbonyl (R³C(O)OCH(Me)OCO—). In some embodiments, thecomposition is one represented by Formula (I) in which X is—O(CR²R⁶)OR³; R² and R⁶ are independently selected from hydrogen,optionally substituted C₁₋₆ alkyl; and R³ is independently selected fromoptionally substituted C₁₋₂₆ alkanoyl or optionally substituted C₁₋₂₆alkenoyl.

In some embodiments, the prodrug composition provided herein allows foran increase in a total amount of exposure of an active form of the drugin the subject's plasma. Thus, in some embodiments, the prodrugdescribed herein as PRX-P6-011 (which includes the (+) isomer offencamfamine) can be used to provide a higher level of the active formof the drug over a desired time period. Such embodiments need not havethe above noted IV vs oral selective activation aspects.

In some embodiments, the prodrug can have the (+) or (−) isomer offencamfamine; however, as shown by the data provided herein, the type ofY group employed for the (+) or (−) isomers can vary and change theproperties of the prodrug. Thus, various fencamfamine isomer prodrugscan have further unique characteristics and/or components, as outlinedherein.

Thus, in some embodiments, prodrugs are provided that delay the time inwhich the active drug (fencamfamine) is made available to the brain (orwithin the plasma). In some embodiments, prodrugs are provided thatallow for higher levels of the active drug to be present in the plasma.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there is a pluralityof definitions for a term herein, those in this section prevail unlessstated otherwise.

The use of the term “N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine”herein is meant to include any of the stereoisomer forms ofN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, including the fourstereoisomers:(1S,2S,3R,4R)—N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine,(1R,2R,3S,4S)—N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine,(1R,2S,3R,4S)—N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine and(1S,2R,3S,4R)—N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine and the saltsand derivatives thereof. The term“N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine” includes all salt forms.N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine is also known by its tradename Fencamfamine®, Glucoenergan®, and Reactivan® (E Merck, Germany).The N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine used in the presentdisclosure can be any stereoisomer ofN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, including, but not limitedto, (1S,2S,3R,4R)—N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine,(1R,2R,3S,4S)—N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine,(1R,2S,3R,4S)—N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine and(1S,2R,3S,4R)—N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine. In someembodiments, the N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine can be amixture of two or more racemates. Depending on the chemical structure ofthe Y group from acyloxyalkoxycarbonyl linked fatty acids, and thiols aswell as the chiral composition of theN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine to which they are attached,the resulting prodrug conjugates can be optically active mixtures ofisomers, racemic mixtures, single isomers or combinations thereof. Thevarious isomers of fencamfamine are depicted below.

RX-002 consists of racemic fencamfamine. The (+)- and (−)-isomersdesignate the optical rotation of the resolved fencamfamine enantiomers.As used herein, the two Exo-phenyl,endo-amino isomers are PRX 002 (+)and (−). One of skill in the art can obtain the desired (+) or (−)enantiomers by chromatography on a chiral column (as outlined in theexamples below). The (+)-enantiomer of fencamfamine is(1S,2S,3R,4R)—N-Ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine. The(−)-enantiomer of fencamfamine is(1R,2R,3S,4S)—N-Ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine. In someembodiments, the (1R,2R,3S,4S)-compound can be used as any of theprodrug compounds provided herein (including any of the methods). Insome embodiments, the (1S,2S,3R,4R)-compound can be used as any of theprodrug compounds provided herein (including any of the methods). Insome embodiments, the (1R,2R,3S,4S)-compound can be used as any of theprodrug compounds provided herein (including any of the methods). Insome embodiments, the (1S,2S,3R,4R)-compound can be used as any of theprodrug compounds provided herein (including any of the methods). Thus,any one of the above isomers can be used as the active in any one of theprodrug arrangements provided herein. In some embodiments, it is one ormore of the Exo isomers noted above. In some embodiments, it is one ormore of the Endo isomers noted above.

As used herein, any “R” group(s) such as, without limitation, R¹, R²,R³, R⁴, R⁵, and R⁶ represent substituents that can be attached to theindicated atom. An R group may be substituted or unsubstituted. If two“R” groups are described as being “taken together” the R groups and theatoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl,heteroaryl or heterocycle. For example, without limitation, if R^(a) andR^(b) of an NR^(a)R^(b) group are indicated to be “taken together,” itmeans that they are covalently bonded to one another to form a ring:

In addition, if two “R” groups are described as being “taken together”with the atom(s) to which they are attached to form a ring as analternative, the R groups may not be limited to the variables orsubstituents defined previously.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group may have 1 to 26 carbon atoms(whenever it appears herein, a numerical range such as “1 to 26” refersto each integer in the given range; e.g., “1 to 26 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 26 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 10 carbon atoms. The alkyl group could also be alower alkyl having 1 to 6 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁-C₆ alkyl” or similar designations. By way ofexample only, “C₁-C₆ alkyl” indicates that there are one to six carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl,pentyl (straight and branched) and hexyl (straight and branched).Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl(straight and branched) and hexyl (straight and branched). The alkylgroup may be substituted or unsubstituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused fashion. Cycloalkyl groups can contain 3 to 10 atoms in thering(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may beunsubstituted or substituted. Typical cycloalkyl groups include, but arein no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

As used herein, “aryl” refers to a carbocyclic (all carbon) mono-cyclicor multi-cyclic aromatic ring system (including fused ring systems wheretwo carbocyclic rings share a chemical bond) that has a fullydelocalized pi-electron system throughout all the rings. The number ofcarbon atoms in an aryl group can vary. For example, the aryl group canbe a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group.Examples of aryl groups include, but are not limited to, benzene,naphthalene and azulene. An aryl group may be substituted orunsubstituted.

As used herein, “alkanoyl” used herein refers to a “carbonyl”substituted with an “alkyl” group, the “alkanoyl” group is covalentlybonded to the parent molecule through the carbon of the “carbonyl”group.

As used herein, “cycloalkanoyl” used herein refers to a “carbonyl”substituted with an “cycloalkyl” group, the “alkanoyl” group iscovalently bonded to the parent molecule through the carbon of the“carbonyl” group.

As used herein, “alkenoyl” used herein refers to a “carbonyl”substituted with an “alkenyl” group, the “alkenoyl” group is covalentlybonded to the parent molecule through the carbon of the “carbonyl”group.

As used herein, “alkynoyl” used herein refers to a “carbonyl”substituted with an “alkynyl” group, the “alkynoyl” group is covalentlybonded to the parent molecule through the carbon of the “carbonyl”group.

As used herein, “alkenyl” refers to a straight or branched hydrocarbonchain containing one or more double bonds. The alkenyl group may have 2to 20 carbon atoms, although the present definition also covers theoccurrence of the term “alkenyl” where no numerical range is designated.The alkenyl group may also be a medium size alkenyl having 2 to 9 carbonatoms. The alkenyl group could also be a lower alkenyl having 2 to 4carbon atoms. The alkenyl group may be designated as “C₂₋₄ alkenyl” orsimilar designations. By way of example only, “C₂₋₄ alkenyl” indicatesthat there are two to four carbon atoms in the alkenyl chain, i.e., thealkenyl chain is selected from the group consisting of ethenyl,propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl,buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl,1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl,buta-1,2,-dienyl, and buta-1,2-dien-4-yl. Typical alkenyl groupsinclude, but are in no way limited to, ethenyl, propenyl, butenyl,pentenyl, and hexenyl, and the like.

As used herein, “alkynyl” refers to a straight or branched hydrocarbonchain containing one or more triple bonds. The alkynyl group may have 2to 20 carbon atoms, although the present definition also covers theoccurrence of the term “alkynyl” where no numerical range is designated.The alkynyl group may also be a medium size alkynyl having 2 to 9 carbonatoms. The alkynyl group could also be a lower alkynyl having 2 to 4carbon atoms. The alkynyl group may be designated as “C2-4 alkynyl” orsimilar designations. By way of example only, “C₂₋₄ alkynyl” indicatesthat there are two to four carbon atoms in the alkynyl chain, i.e., thealkynyl chain is selected from the group consisting of ethynyl,propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and2-butynyl. Typical alkynyl groups include, but are in no way limited to,ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.

The term “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid andphosphoric acid. Pharmaceutical salts can also be obtained by reacting acompound with an organic acid such as aliphatic or aromatic carboxylicor sulfonic acids, for example formic, acetic, succinic, lactic, malic,tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic,p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceuticalsalts can also be obtained by reacting a compound with a base to form asalt such as an ammonium salt, an alkali metal salt, such as a sodium ora potassium salt, an alkaline earth metal salt, such as a calcium or amagnesium salt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine,cyclohexylamine, triethanolamine, ethylenediamine, and salts with aminoacids such as arginine and lysine.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, racemicmixture, diastereomerically pure, diastereomerically enriched, or astereoisomeric mixture. In addition it is understood that, in anycompound described herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof.

Where the compounds disclosed herein have at least one chiral center,they may exist as individual enantiomers and diastereomers or asmixtures of such isomers, including racemates. Separation of theindividual isomers or selective synthesis of the individual isomers isaccomplished by application of various methods which are well known topractitioners in the art. Unless otherwise indicated, all such isomersand mixtures thereof are included in the scope of the compoundsdisclosed herein. Furthermore, compounds disclosed herein may exist inone or more crystalline or amorphous forms. Unless otherwise indicated,all such forms are included in the scope of the compounds disclosedherein including any polymorphic forms. In addition, some of thecompounds disclosed herein may form solvates with water (i.e., hydrates)or common organic solvents. Unless otherwise indicated, such solvatesare included in the scope of the compounds disclosed herein.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensor isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2(deuterium).

It is understood that the compounds described herein can be labeledisotopically. Substitution with isotopes such as deuterium may affordcertain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements. Each chemical element as represented in a compoundstructure may include any isotope of said element. For example, in acompound structure a hydrogen atom may be explicitly disclosed orunderstood to be present in the compound. At any position of thecompound that a hydrogen atom may be present, the hydrogen atom can beany isotope of hydrogen, including but not limited to hydrogen-1(protium) and hydrogen-2 (deuterium). Thus, reference herein to acompound encompasses all potential isotopic forms unless the contextclearly dictates otherwise.

As used herein, the term “prodrug” generally refers to a compound, whichis pharmaceutically acceptable and upon administration is converted to adesired active compound, here fencamfamine. In some embodiments, theprodrug can be therapeutically inactive until cleaved to release theactive compound. The prodrug will contain an “active” component, in thiscase fencamfamine, and a Y moiety as defined. Removal of some or all ofthe Y moiety will convert the prodrug from an inactive form to an activedrug. This is done in the body by a chemical or biological reaction.

In the present disclosure, the prodrug is a conjugate of at least onedrug, N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, and an additional Ymoiety that can be removed and/or altered within the body. Thus, theconjugates of the present disclosure are prodrugs and the prodrugs ofthe present disclosure are conjugates. In some embodiments, the Y moietycan include an acyl group from a carboxylic acid such as a fatty acid,for example. In some embodiments, the Y moiety can be one or more aminoacids, such as one, two, or three valines bonded together as a peptide.

While not a necessary term for describing various embodiments providedhere (such as when explicit structures are shown for the Y moiety,etc.), the term “blocking moiety” denotes a chemical moiety, which maybe removed from a larger prodrug, but when present, reduces and/oralters a property of the active component of the prodrug.

While not a necessary term for describing various embodiments providedhere (such as when explicit structures are shown for the Y moiety,etc.), the term “linker” denotes a chemical moiety, which may link theblocking moiety to the active in a prodrug.

The Y moiety itself may be removable from the prodrug, or the Y moiety(or a part thereof) can remain associated with the active, after theremoval of at least part of the prodrug.

The term “active” is used herein to refer to fencamfamine, and/orN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine (or a particular isomer orcollection thereof) to distinguish it from the prodrug form. Thus, itdoes not necessarily denote any other metabolite or derivative fromfencamfamine (such as whether or not the fencamfamine is altered furtherwhen administered to a subject). The term “active” also encompasses theprodrug compounds that have been activated by proper exposure in vivoand/or in vitro. Thus, the active form of a prodrug may includefencamfamine that is still bonded to some subpart of the prodrug form(for example, whatever remains after the body has removed an adequatesection of the Y moiety). The “activated prodrug” denotes the form ofthe molecule after it has been processed by the body and is in an activeform of fencamfamine. In some embodiments, any of the four isomers offencamfamine noted above can be used in the prodrug, and thus, result inthe isomer for the activated prodrug.

In some embodiments, the prodrug can be easier to administer or processthan the parent or active form of the drug. They may, for instance, bemore bioavailable by oral administration whereas the active drug is not.The prodrug may also have improved solubility in pharmaceuticalcompositions over the active drug. In some embodiments, a prodrug is anN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine conjugate that ismetabolized to reveal the active moiety. In some embodiments, upon invivo administration, a prodrug is chemically converted to thebiologically, pharmaceutically or therapeutically more active form ofthe compound. In some embodiments, a prodrug is enzymaticallymetabolized by one or more steps or processes to the biologically,pharmaceutically or therapeutically active form of the compound. In someembodiments, to produce a prodrug, a pharmaceutically active compound ismodified such that the active compound will be regenerated upon in vivoadministration. In some embodiments, the prodrug is designed to alterthe metabolism or the transport characteristics of a drug in certainembodiments, to mask side-effects or toxicity, to improvebioavailability and/or water solubility, to improve the flavor of adrug, to reduce the risk of abuse, or to alter other characteristics orproperties of a drug in other discrete embodiments.

In some embodiments, the present disclosure provides at least oneprodrug composition comprising at least an active drug conjugated to ablocking moiety and/or linker to form a conjugated molecule or a“conjugate”. The conjugate may comprise at least oneN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine and at least one blockingmoiety, such as an alcohol, amine, acyl group from acyloxyalkoxycarbonylbonded fatty acids, thiol, or derivatives thereof. In some embodiments,the conjugate comprises at least one linker, linking the active drug tothe blocking moiety. In some embodiments, the linker chemically bondsthe N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine to the alcohol, amine,or thiol via one or more covalent bonds. In some embodiments, the linkerserves as part of the blocking moiety and/or is the same as the blockingmoiety. In some embodiments, the linker includes an acyl group from acarboxylic acid.

The term “cancer-related fatigue” encompasses any unusual and persistentsense of tiredness that can occur with cancer and cancer therapy.

The term “supportive oncology” encompasses the treatment of a subjectreceiving or a subject that has received a cancer therapy.

As used herein, phrases such as “decreased,” “reduced,” “diminished” or“lowered” is meant to include at least a 10% change in pharmacologicalactivity with greater percentage changes being preferred for reductionin abuse potential and overdose potential. For instance, the change mayalso be greater than 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%,98%, 99%, or increments therein.

Unless otherwise specified, the term “naturally occurring” refers tooccurring in nature, for example, in bacteria or in a mammal (e.g., ahuman).

The term “abuse” encompasses uses that are inconsistent with a doctor'sor manufacturer's instructions.

As used herein, “in a manner inconsistent with the manufacturer'sinstructions” or similar expression is meant to include, but is notlimited to, consuming amounts greater than amounts described on the druglabel or ordered by a licensed physician, and/or altering by any means(e.g., crushing, breaking, melting, or separating) the dosage form suchthat the composition may be injected, inhaled or smoked instead of beingtaken orally (or according to the instructions).

Depending on the blocking moiety and the alcohol, amine, acyl group froma carboxylic acid, and thiol conjugated toN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine or derivative thereof, theat least one prodrug formed can be either a neutral (uncharged), a freeacid, a free base or a pharmaceutically acceptable anionic or cationicsalt form or salt mixtures with any ratio between positive and negativecomponents. These anionic salt forms can include, but are not limitedto, for example, acetate, l-aspartate, besylate, bicarbonate, carbonate,d-camsylate, l-camsylate, citrate, edisylate, formate, fumarate,gluconate, hydrobromide/bromide, hydrochloride/chloride, d-lactate,l-lactate, d,l-lactate, d,l-malate, l-malate, mesylate, pamoate,phosphate, succinate, sulfate, bisulfate, d-tartrate, l-tartrate,d,l-tartrate, meso-tartrate, benzoate, gluceptate, d-glucuronate,hybenzate, isethionate, malonate, methylsufate, 2-napsylate, nicotinate,nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate,aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate,camphocarbonate, decanoate, hexanoate, cholate, cypionate,dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate(mucate), galacturonate, gallate, gentisate, glutamate, glutamate,glutarate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate,hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate,maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate,oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate,salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate,thiosalicylate, tribrophenate, valerate, valproate, adipate,4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate,thiocyanate, or undecylenate. The cationic salt forms can include, butare not limited to, for example, sodium, potassium, calcium, magnesium,zinc, aluminum, lithium, cholinate, lysinium, ammonium, or tromethamine.

The term “pharmaceutically acceptable carriers” includes, but is notlimited to, 0.01-0.1M and preferably 0.05M phosphate buffer, or inanother embodiment 0.8% saline. Additionally, such pharmaceuticallyacceptable carriers may be in another embodiment aqueous or non-aqueoussolutions, suspensions, and emulsions. Examples of non-aqueous solventsare propylene glycol, polyethylene glycol, vegetable oils such as oliveoil, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, alcoholic/aqueous solutions, emulsions orsuspensions, including saline and buffered media. In some embodiments,the carrier can be a) 10% PEG 400 (v/v)+30% (v/v) HPβCD, 50% w/v+60%(v/v) Sterile Water for Injection or b) 0.1% (v/v) Tween 80+0.5% (w/v)Carboxymethylcellulose in water.

The term “subject” refers to a mammal, such as humans, domestic animals,such as feline or canine subjects, farm animals, such as but not limitedto bovine, equine, caprine, ovine, and porcine subjects, wild animals(whether in the wild or in a zoological garden), research animals, suchas mice, rats, rabbits, goats, sheep, pigs, dogs, and cats, avianspecies, such as chickens, turkeys, and songbirds. The subject can be,for example, a child, such as an adolescent, or an adult.

The term “treatment” refers to any treatment of a pathologic conditionin a subject, such as a mammal, particularly a human, and includes: (i)preventing and/or reducing the risk of a pathologic condition fromoccurring in a subject which may be predisposed to the condition but hasnot yet been diagnosed with the condition and, accordingly, thetreatment constitutes prophylactic treatment for the disease condition;(ii) inhibiting and/or reducing the speed of development of thepathologic condition, e.g., arresting its development; (iii) relievingthe pathologic condition, e.g., causing regression of the pathologiccondition; or (iv) relieving the conditions mediated by the pathologiccondition and/or symptoms of the pathologic condition. Treatment tosubjects who have previously and/or are currently, and/or are about toreceive a cancer therapy are contemplated herein.

The term “therapeutically effective amount” refers to that amount of acompound of the invention that is sufficient to effect treatment, whenadministered to a subject in need of such treatment. The therapeuticallyeffective amount will vary depending upon the subject and diseasecondition being treated, the weight and age of the subject, the severityof the disease condition, the manner of administration and the like,which can readily be determined by one of ordinary skill in the art.

Without being limited to the following theory, some of the embodimentsof the prodrugs/conjugates provided herein undergo enzyme hydrolysis ofthe ester bond in vivo, which subsequently leads to a cascade reactionresulting in provision of N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amineand the respective, metabolites thereof and/or derivatives and/orcomponents thereof. The blocking moieties, such as alcohols, amines,amino acids, acyl group from acyloxyalkoxycarbonyl ((acyloxy)alkylester) bonded fatty acids, thiols, or derivatives thereof, of thepresent disclosure are non-toxic or have very low toxicity at the givendose levels and are preferably known drugs, natural products,metabolites, or GRAS (Generally Recognized As Safe) compounds (e.g.,preservatives, dyes, flavors, etc.) or non-toxic mimetics or derivativesthereof.

It is understood that the methods and combinations described hereininclude crystalline forms (also known as polymorphs, which include thedifferent crystal packing arrangements of the same elemental compositionof a compound), amorphous phases, salts, solvates, and hydrates. In someembodiments, the compounds described herein exist in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, or thelike. In other embodiments, the compounds described herein exist inunsolvated form. Solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and may be formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, or the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

Compounds

In some embodiments, a fencamfamine prodrug is provided. In someembodiments, the prodrug comprises fencamfamine, a Y group conjugated tothe fencamfamine, such as a) a fatty acid or b) at least one amino acid.In some embodiments, the prodrug comprises fencamfamine directly bondedto an amino acid or dipeptide via the amino acid or dipeptide amide bond

In some embodiments, the Y moiety comprises 1-Acyloxyethoxycarbonyl,(R³C(O)OCH(Me)OCO—). In some embodiments, this fencamfamine prodrugcomprises a fatty acid. In some embodiments, the fencamfamine is the002(−) isomer.

In some embodiments, the Y group comprises acyloxymethoxycarbonyl,(R³C(O)OCH₂OCO—). In some embodiments, the fencamfamine is the PRX-002(−) isomer or PRX-002 (+) isomer.

In some embodiments, the fencamfamine prodrug comprises an amino acid ordipeptide directly bonded to fencamfamine via an amide bond. In someembodiments, the at least one amino acid comprises at least two aminoacids as a peptide. In some embodiments, the at least two amino acids isa valine bonded to a valine via a peptide bond. In some embodiments, thefencamfamine is the PRX-002 (+) isomer.

In some embodiments, the fencamfamine component within the prodrugcomprises any one or more of the isomers of fencamfamine as providedherein. In some embodiments, the fencamfamine comprises 1, 2, 3, or 4 ofthe isomers of fencamfamine. In some embodiments, the fencamfamine isonly one of the isomers

In some embodiments the fatty acid is at least C-12 in length. In someembodiments, the fatty acid is at least C-16 in length. In someembodiments, the fatty acid is at least C-18 in length. In someembodiments, the fatty acid is an octadecanoic acid. In someembodiments, the fatty acid is at least C-20 in length. In someembodiments, the fatty acid is at least C-22 in length. In someembodiments, the fatty acid is at least C-24 in length. In someembodiments, the fatty acid is at least C-26 in length.

In some embodiments, a compound is provided having Formula (I):

or a stereoisomer, a pharmaceutically acceptable salt, or solvatethereof, wherein Y is selected from the group consisting of —C(O)X and(A)_(n);wherein X is selected from the group consisting of —OR¹, —NHR¹, —NR¹R⁵,—O(CR²R⁶)OR³, —O(CR²R⁶)SR³, O(CR²R⁶)NR³ and R⁴; wherein R¹ isindependently selected from optionally substituted C₁₋₁₆ alkyl,optionally substituted aryl, and optionally substituted cycloalkyl;wherein R², R⁵, and R⁶ are independently selected from hydrogen,optionally substituted C₁₋₆ alkyl; wherein R³ is independently selectedfrom optionally substituted C₁₋₂₆ alkanoyl; optionally substituted C₁₋₂₆alkenoyl, optionally substituted C₁₋₂₆ alkynoyl; optionally substitutedcycloalkanoyl; wherein R⁴ is independently selected from optionallysubstituted C₁₋₂₆ alkyl; optionally substituted C₁₋₂₆ alkenyl,optionally substituted C₁₋₂₆ alkynyl; optionally substituted cycloalkyl;and wherein (A)_(n) is a peptide unit formed with amino acid unitswherein n is independently 1, 2, 3, or 4.

In some embodiments, R¹ is selected from the group consisting of Me, Et,^(t)Bu, 5-isopropyl-2-methylphenyl, and 2-isopropyl-5-methylphenyl.

In some embodiments, R² and R⁶ are independently selected from the groupconsisting of H and Me.

In some embodiments, R² and R⁶ are independently selected from the groupconsisting of H and Me, R³ is independently selected from optionallysubstituted C₁₋₂₆ alkanoyl.

In some embodiments, R² and R⁶ are independently selected from the groupconsisting of H and Me, R³ is independently selected from optionallysubstituted C₁₋₂₆ alkanoyl, and R³ is from C₁₂ to C₁₈ in chain length.

In some embodiments, R³ is selected from the group consisting of acetyl,pivaloyl, butyryl, capryloyl, decanoyl, lauroyl, and stearoyl.

In some embodiments, X is —O(CHR²)OR³.

In some embodiments, when X is —O(CHR²)OR³, R² is independently selectedfrom hydrogen, optionally substituted C₁₋₆ alkyl.

In some embodiments, R⁴ is —CH₂CH₂COOH.

In some embodiments, (A)_(n) is selected from the group consisting ofVal, Lys, Gly, Gly-Gly, Val-Val, Gly-Ala, Phe, Phe-Phe, Ala-Gly, andLys-Lys.

In some embodiments, the compound of Formula (I) is selected from thegroup of at least one of the following:

Some of the above formula can also be depicted by the followingstructures:

Some of the above formula can also be described by the followingstructures:

or a stereoisomer, or a pharmaceutically acceptable salt, ester, orsolvate thereof. In some embodiments, any one or more of the formulaidentified above can be used in any of the compositions and/or methodsprovided herein.

In some embodiments, a pharmaceutical composition comprising thecompound of any embodiment provided herein regarding fencamfamine and apharmaceutically acceptable carrier is provided.

In some embodiments, one or more prodrug compositions of the presentdisclosure will surprisingly exhibit a slower rate of release over timeas compared to unmodified fencamfamine.

In some embodiments, one or more prodrug compositions of the presentdisclosure provides reduced side effects as compared to unconjugatedfencamfamine when administered at equimolar doses, and also providereduced abuse potential as compared to unconjugated fencamfamine. Insome embodiments, after administration of the prodrug of fencamfaminevia IV, the amount of fencamfamine present in the subject's plasma is atleast 5% less than if fencamfamine had been administered to the subjectorally, for example, at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 91,92, 93, 94, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6,99.7, 99.8, 99.9% or less, or 100%, including any range above any one ofthe preceding values and any range between any two of the precedingvalues.

In some embodiments one or more fencamfamine prodrug compositions of thepresent disclosure provides an amount sufficient to provide an extendedT_(max) when compared to unconjugated fencamfamine when administered atequimolar doses, and/or provides an equivalent T_(max) when compared tounconjugated fencamfamine when administered at equimolar doses.

In some embodiments, one or more fencamfamine prodrug compositions ofthe present disclosure provides an increased level of the active drug(fencamfamine) in the plasma, when the prodrug compound is administeredorally, in comparison to the amount of active present in the plasma whenfencamfamine itself is administered (not as a prodrug). Thus, in someembodiments, the composition results in a higher level of active in theplasma, than would be present if the active itself had beenadministered. In some embodiments, the increase is at least 10, 20, 30,40, 50, 60, 70, 80, 90, 100, 150, 200, 400% or more at any given pointin time.

Compounds of Formula (I) described herein can be prepared in variousways. General synthetic routes to compounds of Formula (I) are shown anddescribed herein. The routes shown and described herein are illustrativeonly and are not intended, nor are they to be construed, to limit thescope of the claims in any manner whatsoever. Those skilled in the artwill be able to recognize modifications of the disclosed syntheses andto devise alternate routes based on the disclosures herein; all suchmodifications and alternate routes are within the scope of the claims.In some embodiments, the fatty acid bonded prodrug is prepared by thereaction of PRX-002 with chloromethyl chloroformate or 1-chloroethylchloroformate, followed by the reaction with various carboxylic acids inthe presence of cesium carbonate and potassium iodide in DMF, asillustrated in the scheme 4.2. In some embodiments, the amino acidbonded prodrug is prepared by the coupling of PRX-002 with N-Bocprotected amino acid and then removal of Boc group under acidicconditions. Further coupling with another N-Boc protected amino acid andsubsequent deprotection provided dipeptide bonded prodrugs, asillustrated in Scheme 4.3.

Depending upon the substituents present, the compounds can be in a formof a pharmaceutically acceptable salt. The terms “pharmaceuticallyacceptable salt” as used herein are broad terms, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to salts prepared from pharmaceuticallyacceptable, non-toxic acids or bases. Suitable pharmaceuticallyacceptable salts include metallic salts, e.g., salts of aluminum, zinc,alkali metal salts such as lithium, sodium, and potassium salts,alkaline earth metal salts such as calcium and magnesium salts; organicsalts, e.g., salts of lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), procaine, and tris; salts of free acids and bases;inorganic salts, e.g., sulfate, hydrochloride, and hydrobromide; andother salts which are currently in widespread pharmaceutical use and arelisted in sources well known to those of skill in the art, such as, forexample, The Merck Index. Any suitable constituent can be selected tomake a salt of the therapeutic agents discussed herein, provided that itis non-toxic and does not substantially interfere with the desiredactivity.

The compounds of preferred embodiments can include isomers, racemates,optical isomers, exo-isomers, endo-isomers, enantiomers, diastereomers,tautomers, and cis/trans conformers. All such isomeric forms areincluded within preferred embodiments, including mixtures thereof. Asdiscussed above, the compounds of preferred embodiments may have chiralcenters, for example, they may contain asymmetric carbon atoms and maythus exist in the form of enantiomers or diastereoisomers and mixturesthereof, e.g., racemates. Asymmetric carbon atom(s) can be present inthe (R)- or (S)-configuration, or can be present as mixtures of the (R)-and (S)-forms. N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine can exist asthe Exo-phenyl,endo-amino and endo-phenyl,exo-amino substituteddiastereomers. Each diastereomer is a pair of enantiomers. For e.g. theExo-phenyl,endo-amino diastereomer is a mixture of the following twoenantiomers, namely,(1S,2S,3R,4R)—N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine and(1R,2R,3S,4S)—N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine. Thefollowing are enantiomeric forms of the Exo-phenyl,endo-amino isomer ofthe compounds of Formula (I):

wherein Y=(L)-Val, (L)-Ala, Gly, (L)-Lys, Gly-Gly, (L)-Val-(L)-Val,(L)-Phe-(L)-Phe, (L)-Ala-Gly, (L)-Phe, Gly-(L)-Ala. In some embodiments,Y=Acyl, succinyl, alkyl-carbamoyl, aryl-oxycarbonyl, alkylsubstituted-aryl-oxycarbonyl, analogues of (acyloxy)alkyl carbamates,alkyl substituted analogues of (acyloxy)alkyl carbamates, etc.

The compounds can be in amorphous form, or in crystalline forms. Thecrystalline forms of the compounds of preferred embodiments can exist aspolymorphs, which are included in preferred embodiments. In addition,some of the compounds of preferred embodiments may also form solvateswith water or other organic solvents. Such solvates are similarlyincluded within the scope of the preferred embodiments.

In some embodiments, a fencamfamine prodrug is provided that comprisesfencamfamine; a linker conjugated to the fencamfamine; and a fatty acidor at least one amino acid conjugated to the linker. In someembodiments, the moiety Y described herein can replace the linker andthe fatty acid and/or at least one amino acid conjugated to the linker.In some embodiments, the linker comprises (acyloxy)ethyl ester linkage(—C(O)OCH(Me)O—). In some embodiments, the fencamfamine prodrugcomprises a fatty acid. In some embodiments, the linker comprises(acyloxy)methyl ester linkage (—C(O)OCH₂O—). In some embodiments, thefencamfamine prodrug comprises a fatty acid. In some embodiments, thefatty acid is at least C12 in length. In some embodiments, the fattyacid is at least C16 in length. In some embodiments, the fatty acid isat least C18 in length. In some embodiments, the fencamfine prodrugcomprises an amino acid conjugated to the linker. In some embodiments,the at least one amino acid comprises at least two amino acids as apeptide. In some embodiments, the at least two amino acids is a valinelinked to a valine. It is noted that, when, specified, the Y moietydescription provided herein provides an alternative manner of describingvarious embodiments of the invention, without the need of separating themolecule into linker and blocker sections. Thus, the Y moietydescription need not separately describe the linker and blockercomponents.

Embodiments of Pharmaceutical Compositions

In some embodiments, one can administer the prodrugs in an oral unitdosage form; however, other routes of administration are also possible.For various embodiments, contemplated routes of administration includebut are not limited to oral, parenteral, intravenous, and subcutaneous.The prodrugs can be formulated into liquid preparations for, e.g., oraladministration. Suitable forms include suspensions, syrups, elixirs, andthe like. Particularly preferred unit dosage forms for oraladministration include tablets and capsules. Unit dosage formsconfigured for administration once a day can be employed; however, insome embodiments it can be desirable to configure the unit dosage formfor administration twice a day, or more.

For oral administration, the pharmaceutical compositions can be providedas a tablet, aqueous or oil suspension, dispersible powder or granule,emulsion, hard or soft capsule, syrup or elixir. Compositions intendedfor oral use can be prepared according to any method known in the artfor the manufacture of pharmaceutical compositions and can include oneor more of the following agents: sweeteners, flavoring agents, coloringagents and preservatives. Aqueous suspensions can contain the prodrug inadmixture with excipients suitable for the manufacture of aqueoussuspensions.

Formulations for oral use can also be provided as hard gelatin capsules,wherein the prodrug(s) are mixed with an inert solid diluent, such ascalcium carbonate, calcium phosphate, or kaolin, or as soft gelatincapsules. In soft capsules, the prodrugs can be dissolved or suspendedin suitable liquids, such as water or an oil medium, such as peanut oil,olive oil, fatty oils, liquid paraffin, or liquid polyethylene glycols.Stabilizers and microspheres formulated for oral administration can alsobe used. Capsules can include push-fit capsules made of gelatin, as wellas soft, sealed capsules made of gelatin and a plasticizer, such asglycerol or sorbitol. The push-fit capsules can contain the activeingredient in admixture with fillers such as lactose, binders such asstarches, and/or lubricants such as talc or magnesium stearate and,optionally, stabilizers.

Tablets can be uncoated or coated by known methods to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period of time. For example, atime delay material such as glyceryl monostearate can be used. Whenadministered in solid form, such as tablet form, the solid formtypically comprises from about 0.001 wt. % or less to about 50 wt. % ormore of active ingredient(s), preferably from about 0.005, 0.01, 0.02,0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, or 1 wt. % to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20,25, 30, 35, 40, or 45 wt. %.

Tablets can contain the active ingredients in admixture with non-toxicpharmaceutically acceptable excipients including inert materials. Forexample, a tablet can be prepared by compression or molding, optionally,with one or more additional ingredients. Compressed tablets can beprepared by compressing in a suitable machine the active ingredients ina free-flowing form such as powder or granules, optionally mixed with abinder, lubricant, antiadherents, coatings, disintegrants, fillers,flavors and colors, preservatives, sorbens, sweeteners, inert diluent,surface active or dispersing agent. Molded tablets can be made bymolding, in a suitable machine, a mixture of the powdered prodrugmoistened with an inert liquid diluent.

In some embodiments, each tablet or capsule contains from about 1 mg orless to about 1,000 mg or more of an prodrug of the preferredembodiments, more preferably from about 10, 20, 30, 40, 50, 60, 70, 80,90, or 100 mg to about 150, 200, 250, 300, 350, 400, 450, 500, 550, 600,650, 700, 750, 800, or 900 mg. Most preferably, tablets or capsules areprovided in a range of dosages to permit divided dosages to beadministered. A dosage appropriate to the patient and the number ofdoses to be administered daily can thus be conveniently selected. Incertain embodiments it can be preferred to incorporate two or more ofthe therapeutic agents to be administered into a single tablet or otherdosage form (e.g., in a combination therapy); however, in otherembodiments it can be preferred to provide the therapeutic agents inseparate dosage forms.

Suitable inert materials include diluents, such as carbohydrates,mannitol, lactose, anhydrous lactose, cellulose, sucrose, modifieddextrans, starch, and the like, or inorganic salts such as calciumtriphosphate, calcium phosphate, sodium phosphate, calcium carbonate,sodium carbonate, magnesium carbonate, and sodium chloride.Disintegrants or granulating agents can be included in the formulation,for example, starches such as corn starch, alginic acid, sodium starchglycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin,sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose,natural sponge and bentonite, insoluble cationic exchange resins,powdered gums such as agar, karaya or tragacanth, or alginic acid orsalts thereof.

Binders can be used to form a hard tablet. Binders include materialsfrom natural products such as acacia, tragacanth, starch and gelatin,methyl cellulose, ethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, and the like.

Lubricants, such as octadecanoic acid or magnesium or calcium saltsthereof, polytetrafluoroethylene, liquid paraffin, vegetable oils andwaxes, sodium lauryl sulfate, magnesium lauryl sulfate, polyethyleneglycol, starch, talc, pyrogenic silica, hydrated silicoaluminate, andthe like, can be included in tablet formulations.

Surfactants can also be employed, for example, anionic detergents suchas sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctylsodium sulfonate, cationic such as benzalkonium chloride or benzethoniumchloride, or nonionic detergents such as polyoxyethylene hydrogenatedcastor oil, glycerol monostearate, polysorbates, sucrose fatty acidester, methyl cellulose, or carboxymethyl cellulose.

Controlled release formulations can be employed wherein prodrug isincorporated into an inert matrix that permits release by eitherdiffusion or leaching mechanisms. Slowly degenerating matrices can alsobe incorporated into the formulation. Other delivery systems can includetimed release, delayed release, or sustained release delivery systems.

Coatings can be used, for example, nonenteric materials such as methylcellulose, ethyl cellulose, hydroxyethyl cellulose, methylhydroxy-ethylcellulose, hydroxypropyl cellulose, hydroxypropyl-methyl cellulose,sodium carboxy-methyl cellulose, providone and the polyethylene glycols,or enteric materials such as phthalic acid esters. Dyestuffs or pigmentscan be added for identification or to characterize differentcombinations of prodrug doses.

In some embodiments, the pharmaceutical compositions of the prodrugs canbe isotonic with the blood or other body fluid of the recipient. Theisotonicity of the compositions can be attained using sodium tartrate,propylene glycol or other inorganic or organic solutes. Sodium chlorideis particularly preferred. Buffering agents can be employed, such asacetic acid and salts, citric acid and salts, boric acid and salts, andphosphoric acid and salts. Parenteral vehicles include sodium chloridesolution, Ringer's dextrose, dextrose and sodium chloride, lactatedRinger's or fixed oils. Intravenous vehicles include fluid and nutrientreplenishers, electrolyte replenishers (such as those based on Ringer'sdextrose), and the like.

Viscosity of the pharmaceutical compositions can be maintained at theselected level using a pharmaceutically acceptable thickening agent. Insome embodiments, methylcellulose can be used. Other suitable thickeningagents include, for example, xanthan gum, carboxymethyl cellulose,hydroxypropyl cellulose, carbomer, and the like. The preferredconcentration of the thickener will depend upon the thickening agentselected. An amount is preferably used that will achieve the selectedviscosity. Viscous compositions are normally prepared from solutions bythe addition of such thickening agents.

In some embodiments, a pharmaceutically acceptable preservative can beemployed to increase the shelf life of the pharmaceutical compositions.Benzyl alcohol can be suitable, although a variety of preservativesincluding, for example, parabens, thimerosal, chlorobutanol, orbenzalkonium chloride can also be employed. A suitable concentration ofthe preservative is typically from about 0.02% to about 2% based on thetotal weight of the composition, although larger or smaller amounts canbe desirable depending upon the agent selected. Reducing agents, asdescribed above, can be advantageously used to maintain good shelf lifeof the formulation.

The prodrugs can be in admixture with a suitable carrier, diluent, orexcipient such as sterile water, physiological saline, glucose, or thelike, and can contain auxiliary substances such as wetting oremulsifying agents, pH buffering agents, gelling or viscosity enhancingadditives, preservatives, flavoring agents, colors, and the like,depending upon the route of administration and the preparation desired.See, e.g., “Remington: The Science and Practice of Pharmacy”, LippincottWilliams & Wilkins; 20th edition (Jun. 1, 2003) and “Remington'sPharmaceutical Sciences,” Mack Pub. Co.; 18^(th) and 19^(th) editions(December 1985, and June 1990, respectively). Such preparations caninclude complexing agents, metal ions, polymeric compounds such aspolyacetic acid, polyglycolic acid, hydrogels, dextran, and the like,liposomes, microemulsions, micelles, unilamellar or multilamellarvesicles, erythrocyte ghosts or spheroblasts. Suitable lipids forliposomal formulation include, without limitation, monoglycerides,diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bileacids, and the like. The presence of such additional components caninfluence the physical state, solubility, stability, rate of in vivorelease, and rate of in vivo clearance, and are thus chosen according tothe intended application, such that the characteristics of the carrierare tailored to the selected route of administration.

When administered orally in liquid form, a liquid carrier such as water,petroleum, oils of animal or plant origin such as peanut oil, mineraloil, soybean oil, or sesame oil, or synthetic oils can be added to theactive ingredient(s). Physiological saline solution, dextrose, or othersaccharide solution, or glycols such as ethylene glycol, propyleneglycol, or polyethylene glycol are also suitable liquid carriers. Thepharmaceutical compositions can also be in the form of oil-in-wateremulsions. The oily phase can be a vegetable oil, such as olive orarachis oil, a mineral oil such as liquid paraffin, or a mixturethereof. Suitable emulsifying agents include naturally-occurring gumssuch as gum acacia and gum tragacanth, naturally occurring phosphatides,such as soybean lecithin, esters or partial esters derived from fattyacids and hexitol anhydrides, such as sorbitan mono-oleate, andcondensation products of these partial esters with ethylene oxide, suchas polyoxyethylene sorbitan mono-oleate. The emulsions can also containsweetening and flavoring agents.

Pulmonary delivery can also be employed. The compound is delivered tothe lungs while inhaling and traverses across the lung epithelial liningto the blood stream. A wide range of mechanical devices designed forpulmonary delivery of therapeutic products can be employed, includingbut not limited to nebulizers, metered dose inhalers, and powderinhalers, all of which are familiar to those skilled in the art. Thesedevices employ formulations suitable for the dispensing of compound.Typically, each formulation is specific to the type of device employedand can involve the use of an appropriate propellant material, inaddition to diluents, adjuvants, and/or carriers useful in therapy.

The compound and/or other optional active ingredients can be preparedfor pulmonary delivery in particulate form with an average particle sizeof from 0.1 μm or less to 10 μm or more, more preferably from about 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 μm to about 1.0, 1.5, 2.0, 2.5,3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, or 9.5μm. Pharmaceutically acceptable carriers for pulmonary delivery ofprodrug include carbohydrates such as trehalose, mannitol, xylitol,sucrose, lactose, and sorbitol. Other ingredients for use informulations can include DPPC, DOPE, DSPC, and DOPC. Natural orsynthetic surfactants can be used, including polyethylene glycol anddextrans, such as cyclodextran. Bile salts and other related enhancers,as well as cellulose and cellulose derivatives, and amino acids can alsobe used. Liposomes, microcapsules, microspheres, inclusion complexes,and other types of carriers can also be employed.

Pharmaceutical formulations suitable for use with a nebulizer, eitherjet or ultrasonic, typically comprise the prodrug dissolved or suspendedin water at a concentration of about 0.01 or less to 100 mg or more ofprodrug per mL of solution, preferably from about 0.1, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10 mg to about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,70, 75, 80, 85, or 90 mg per mL of solution. The formulation can alsoinclude a buffer and a simple sugar (e.g., for protein stabilization andregulation of osmotic pressure). The nebulizer formulation can alsocontain a surfactant, to reduce or prevent surface induced aggregationof the prodrug caused by atomization of the solution in forming theaerosol.

Formulations for use with a metered-dose inhaler device generallycomprise a finely divided powder containing the active ingredientssuspended in a propellant with the aid of a surfactant. The propellantcan include conventional propellants, such as chlorofluorocarbons,hydrochlorofluorocarbons, hydrofluorocarbons, and hydrocarbons.Preferred propellants include trichlorofluoromethane,dichlorodifluoromethane, dichlorotetrafluoroethanol,1,1,1,2-tetrafluoroethane, and combinations thereof. Suitablesurfactants include sorbitan trioleate, soya lecithin, and oleic acid.

Formulations for dispensing from a powder inhaler device typicallycomprise a finely divided dry powder containing prodrug, optionallyincluding a bulking agent, such as lactose, sorbitol, sucrose, mannitol,trehalose, or xylitol in an amount that facilitates dispersal of thepowder from the device, typically from about 1 wt. % or less to 99 wt. %or more of the formulation, preferably from about 5, 10, 15, 20, 25, 30,35, 40, 45, or 50 wt. % to about 55, 60, 65, 70, 75, 80, 85, or 90 wt. %of the formulation.

When a compound is administered by intravenous, parenteral, or otherinjection, it is preferably in the form of a pyrogen-free, parenterallyacceptable aqueous solution or oleaginous suspension. Suspensions can beformulated according to methods well known in the art using suitabledispersing or wetting agents and suspending agents. The preparation ofacceptable aqueous solutions with suitable pH, isotonicity, stability,and the like, is within the skill in the art. A preferred pharmaceuticalcomposition for injection preferably contains an isotonic vehicle suchas 1,3-butanediol, water, isotonic sodium chloride solution, Ringer'ssolution, dextrose solution, dextrose and sodium chloride solution,lactated Ringer's solution, or other vehicles as are known in the art.In addition, sterile fixed oils can be employed conventionally as asolvent or suspending medium. For this purpose, any bland fixed oil canbe employed including synthetic mono or diglycerides. In addition, fattyacids such as oleic acid can likewise be used in the formation ofinjectable preparations. The pharmaceutical compositions can alsocontain stabilizers, preservatives, buffers, antioxidants, or otheradditives known to those of skill in the art.

The duration of the injection can be adjusted depending upon variousfactors, and can comprise a single injection administered over thecourse of a few seconds or less, to 0.5, 0.1, 0.25, 0.5, 0.75, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, or 24 hours or more of continuous intravenous administration.

Kit Embodiments

In some embodiments, the prodrugs can be provided to an administeringphysician, other health care professional, or subject in the form of akit. The kit is a package which houses a container which contains thecompound in a suitable pharmaceutical composition, and instructions foradministering the pharmaceutical composition to a subject. The kit canoptionally also contain one or more additional therapeutic agents, e.g.,chemotherapeutics currently employed for treating a cancer as describedherein. For example, a kit containing one or more compositionscomprising one or more prodrug in combination with one or moreadditional chemotherapeutic agents can be provided, or separatepharmaceutical compositions containing a prodrug of the preferredembodiments and additional therapeutic agents can be provided. The kitcan also contain separate doses of a prodrug for serial or sequentialadministration. The kit can optionally contain one or more diagnostictools and instructions for use. The kit can contain suitable deliverydevices along with instructions for administering the prodrug(s) and anyother therapeutic agent. The kit can optionally contain instructions forstorage, reconstitution (if applicable), and administration of any orall therapeutic agents included. The kits can include a plurality ofcontainers reflecting the number of administrations to be given to asubject. The kit can also include different types of fencamfamineprodrugs, as described herein. In some embodiments, the instructions canbe inline with one or more of the methods outlined herein.

Methods of Use and Treatment

In some embodiments one or more prodrug compositions can be used fortreating cancer-related fatigue by administering an effective amount ofthe composition to a subject in need thereof. In some embodiments, anyof the prodrugs provided herein can be used. In some embodiments, thesubject is human. In some embodiments, the subject has or had cancer. Insome embodiments, the subject has gone through one or more rounds of acancer therapy. In some embodiments, the subject has or has beendiagnosed with cancer related fatigue.

In some embodiments, such as cancer-related fatigue, chronic fatiguesyndrome, major depressive disorder, narcolepsy, advanced Parkinson'sDisease, attention deficit-hyperactivity disorder (ADHD),substance-abuse disorders or Binge-eating disorder, the subject to betreated is in need of one or more of the benefits or properties offencamfamine. In some embodiments, such as Alzheimer's disease, such asapathy in Alzheimer's disease and cognitive impairment in Alzheimer'sdisease and dopamine responsive dystonia the subject to be treated is inneed of one or more of the benefits or properties of fencamfamine.

In some embodiments, the subject to be treated is at risk of abusingfencamfamine. In some embodiments, the risk is that the subject will orhas taken fencamfamine via IV or injection. In some embodiments, some ofthe embodiments provided herein allow for a reduced risk that thesubject will, or will repeat an IV administration of the prodrug.

In some embodiments, via the use of one or more of the prodrugcompositions provided herein, one, can provide to a subject a sufficientlevel of fencamfamine via oral administration, but not via IVadministration (at least the amount of activated compound in thesubject's plasma will be lower if given via IV than if given orally).

In some embodiments one or more prodrug compositions can be used fortreating neurological disorders such as Parkinson's disease, Alzheimer'sdisease, and/or dopamine responsive dystonia by administering aneffective amount of the composition to a subject in need thereof.

In some embodiment, the present disclosure provides at least one prodrugcomposition having an extended or controlled release profile as measuredby plasma concentrations of released fencamfamine when compared tounconjugated fencamfamine when administered orally at equimolar doses.In some embodiments, the plasma concentration of fencamfamine releasedfrom the prodrug increases more slowly and over a longer period of timeafter oral administration, resulting in a delay in peak plasmaconcentration of released fencamfamine and in a longer duration ofaction when compared to unconjugated fencamfamine. In some embodiments,this can be the PRX-P6-011 using the + isomer) and/or PRX-P5-006 (usingthe − isomer) and/or PRX-P4-003 (using the − isomer).

In some embodiments, the subject is mammalian. In some embodiment, thesubject is human.

In some embodiments, one or more of the fencamfamine produgs providesfor an increase in an amount of fencamfamine present in a subject,compared to the administration of fencamfamine to the subject. Thus, insome embodiments, a method is provided for providing to a subjectgreater levels of fencamfamine by administering a prodrug offencamfamine as described herein. In some embodiments, this can be aprodrug with a valine-valine Y moiety. In some embodiments, this can bethe PRX-P6-011 compound.

In some embodiments, two or more of the fencamfamine prodrugs providedherein are combined into a composition of two or more of thefencamfamine prodrugs provided herein are administered to a subject. Thetwo or more fencamfamine prodrugs can be administered serially or inparallel (either at overlapping volumes or over the same period oftime). In some embodiments, this combination can be a first prodrug thatprovides delayed release and/or effects, while a second produg andprovide a greater level of availability of the active than would bepresent if fencamfamine were given directly. For example, this can beachieved by having PRX-P5-006 as the first prodrug, to provide a delayedonset and/or abuse-resistance, while having PRX-P6-011 as the secondprodrug so as to provide a greater initial and/or sustained level offencamfamine isomer compared to parent.

In some embodiments, the prodrugs or conjugate compositions of thepresent disclosure can be administered orally and, upon administration,release N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, derivativesthereof (which would include some part of the Y moiety from the prodrug)or combinations thereof, after being hydrolyzed in the body. Withoutbeing bound by any particular theory, in some embodiments, theacyloxyalkoxycarbonyl bonded fatty acids that are conjugated to theN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, derivatives thereof orcombinations thereof, of the present disclosure are naturally occurringmetabolites, pharmaceutically active compounds or mimetics thereof orderivatives thereof. The prodrugs or conjugates of the presentdisclosure can be recognized by physiological systems resulting inhydrolysis and release of N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(or a derivative thereof), when taken orally, but not when taken via IVinjection.

Some embodiments of the prodrugs are believed to have no or limitedpharmacological activity themselves and consequently may follow ametabolic pathway that differs from the parent drug (i.e.,N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine). Without being bound byany theory, by choosing a suitable blocking moiety, such as an acylgroup from a carboxylic acid, the release ofN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine into the systemiccirculation can be controlled even when the prodrug is administered viaroutes other than oral administration.

In some embodiments, the prodrugs ofN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, derivatives thereof orcombinations thereof, of the present disclosure surprisingly releaseN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, derivatives thereof orcombinations thereof, similar to free or unmodifiedN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine. That is, the activatedprodrug is identical or similar in its properties to the original formof the drug (fencamfamine).

In some embodiments, the at least one conjugatedN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, derivatives thereof orcombinations thereof, of the present disclosure are believed to bereleased in a controlled or sustained form.

In some embodiments, the at least one prodrug or conjugate generates aT_(max) value of released N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-aminethat is longer than the T_(max) value produced by “unconjugated”N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine (i.e., the active) whenadministered at equimolar doses. In another embodiment, the at least oneprodrug or conjugate generates a T_(max) value of releasedN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine that is similar to theT_(max) value produced by unconjugatedN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, when administered atequimolar doses.

In some embodiments, the AUC is about 50% or smaller of the AUC ofunconjugated N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, whenadministered intranasally or intravenously at equimolar doses, forexample about 50% to about 0.1%, alternatively from about 25% to about0.1%, alternatively from about 50% to about 1%, including, but notlimited to, about 50%, about 40%, about 30%, about 20%, about 10%, about1% or any amounts in between, in increments of about 0.5%, about 1%,about 2%, about 2.5%, about 5% or about 10%.

In some embodiments, the compounds, prodrugs, compositions and/ormethods of the present disclosure provide reduced potential foroverdose, reduced potential for abuse and/or improve the characteristicsof N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, derivatives thereof orcombinations thereof with regard to toxicities or suboptimal releaseprofiles.

In some embodiments, some compositions may have no or a substantiallydecreased pharmacological activity when administered through intravenousinjection or intranasal routes of administration. However, they remainorally bioavailable. Without being limited to the below theory, overdoseprotection may occur due to the conjugates being exposed to differentenzymes and/or metabolic pathways after oral administration whereby theconjugate of the present disclosure is exposed to the gut and first-passmetabolism as opposed to exposure to enzymes in the circulation ormucosal membranes in the nose which limits the ability of theN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, derivatives thereof orcombinations thereof, from being released from the conjugate. Therefore,in some embodiments, abuse resistance is provided by limiting theeffectiveness of alternative routes of administration. Again, not beingbound by any particular theory, the bioavailability can be a result ofthe hydrolysis of the chemical linkage (such as a covalent linkage)following oral administration. In at least one alternative embodiment,the prodrugs of the present disclosure are envisioned to not hydrolyzeor to hydrolyze at a reduced rate or to a limited extent via non-oralroutes. As a result, they are believed to not generate high plasma orblood concentrations of releasedN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine when injected or snortedcompared to free N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amineadministered through these routes.

In some embodiments, at least some compositions of the presentdisclosure comprising the prodrugs of one or moreN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, derivatives thereof orcombinations thereof, are resistant to abuse by parenteral routes ofadministration, such as intravenous “shooting,” or intranasal“snorting,” that are often employed during illicit use. In at least somecontemplated alternative embodiments, release ofN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, derivatives thereof orcombinations thereof, is reduced when the composition of the presentdisclosure is delivered by parenteral routes. In some embodiments, theconjugates, since they are believed to include covalently boundN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, derivatives thereof orcombinations thereof, are not able to be physically manipulated torelease the N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, derivativesthereof or combinations thereof, from the conjugatedN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine, derivatives thereof orcombinations thereof, by methods, for example, of grinding up orcrushing of solid forms. In some embodiments, some compositionscontaining prodrugs or conjugates of the present disclosure preferablyhave no or a substantially decreased pharmacological activity whenadministered through injection or intranasal routes of administration.However, they remain orally bioavailable.

In some embodiments, the present disclosure provides a stimulant basedtreatment modality and dosage form for certain disorders requiring thestimulation of the CNS such as, cancer-related fatigue, chronic fatiguesyndrome, major depressive disorder, narcolepsy, advanced Parkinson'sDisease, ADHD, substance-abuse disorders, binge-eating disorderAlzheimer's disease (such as apathy in Alzheimer's disease), or DopamineResponsive Dystonia.

In some embodiments, the at least one composition or prodrug of thepresent disclosure can be used in one or more methods of treating apatient having at least one disease, disorder or condition requiringstimulation of the central nervous system of one or more patients,comprising orally administering a pharmaceutically effective amount ofthe at least one composition or prodrug.

Certain compounds, compositions and methods provided herein can be usedto treat a number of disorders such as those requiring the stimulationof the CNS such as, cancer-related fatigue i.e. fatigue caused due tochemotherapy induced anemia, fatigue caused due to radiation therapy,depression, chronic fatigue syndrome, or major depressive disordernarcolepsy. In some embodiments, certain compounds, compositions andmethods provided herein can be used to treat Alzheimer's disease, suchas apathy in Alzheimer's disease and cognitive impairment in Alzheimer'sdisease. In some embodiments, certain compounds, compositions andmethods provided herein can be used to treat dopamine responsivedystonia.

In some embodiments, the prodrug provided herein is mostly (at least50%, for example, at least 60, at least 70, at least 80, at least 90, atleast 91, at least 92, at least 93, at least 94, at least 95, at least96, at least 97, at least 98, at least 99, at least 100% metabolized byan oral route, over an IV route. In some embodiments, the prodrugcomponent (the non-active) or any hydrolyzed products, are not toxic. Insome embodiments, there is a good AUC (at least about 50% compared tothe active). In some embodiments, the product allows for once a daydosing (or is configured in an amount for such dosing). In someembodiments, the product has an abuse resistant profile (delayed Tmaxand/or low Cmax). In some embodiments, the prodrug, has a relatively lowIV conversion rate (compared to oral). In some embodiments, the prodrugmoiety is safe for human consumption.

For convenience, Table 1 displays a listing of the various chemicalnames with the names used herein of the actives and prodrugs, as well asthe structures. The structures in Table 1 do not necessarily depict theabsolute configurations of (+)- and(−)-N-Ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine.

In some embodiments, any one or more of the prodrugs provided in Table 1can be part of any composition and/or formulation and/or method providedherein.

TABLE 1 COMPOUNDS Compound Fencamfamne Identification Isomer ChemicalName Structure PRX-001 (±) N-Ethyl-3- phenylbicyclo[2.2.1]heptan-2-amine (Racemic mixture)

PRX-002 (+) N-Ethyl-3- phenylbicyclo[2.2.1]heptan- 2-amine ((+)-isomer)

PRX-002 (−) N-Ethyl-3- phenylbicyclo[2.2.1]heptan- 2-amine ((−)-isomer)

PRX-P1-001 (±) N-Succinyl-N-ethyl-3- phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P1-005 (−) N-Lysyl-(−)-N-ethyl-3- phenylbicyclo[2.2.1]heptan-2-amine

PRX-P1-006 (±) N-Valyl-N-ethyl-3- phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P1-011 (−) N-Acetyl-(−)-N-ethyl-3- phenylbicyclo[2.2.1]heptan-2-amine

PRX-P1-012 (−) N-Glycyl-(−)-N-ethyl-3- phenylbicyclo[2.2.1]heptan-2-amine

PRX-P1-013 (−) N-Phenylalanyl-(−)-N-ethyl-3- phenylbicyclo[2.2.1]heptan-2-amine

PRX-P2-001 (±) N-Ethoxycarbonyl-N-ethyl-3- phenylbicyclo[2.2.1]heptan-2-amine

PRX-P3-002 (−) N-(5-Isopropyl-2- methylphenoxycarbonyl)-(−)- N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P3-004 (−) N-(2-Isopropyl-5- methylphenoxycarbonyl)-(−)- N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P4-001 (−) N- (Acetoxymethoxycarbonyl)- (−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P4-002 (−) N- (Decanoyloxy- methoxycarbonyl)- (−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P4-003 (−) N- (Octadecanoyloxy- methoxycarbonyl)- (−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P4-004 (−) N-((Z)-Octadec-9- enoyloxymethoxy- carbonyl)-(−)-N-ethyl-3- phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P5-001 (−) N-(1- Acetoxyethoxycarbonyl)- (−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P5-002 (−) N-(1- Decanoyloxyethoxycarbonyl)- (−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P5-003 (−) N-(1- Butanoyloxyethoxycarbonyl)- (−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P5-004 (−) N-(1- Octanoyloxyethoxycarbonyl)- (−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P5-005 (−) N-(1- Dodecanoyloxy- ethoxycarbonyl)- (−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P5-006 (−) N-(1- Octadecanoyloxy- ethoxycarbonyl)- (−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P5-007 (−) N-(1-(2,2- Dimethylpropionyloxy) ethoxycarbonyl)-(−)-N-ethyl-3- phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P5-008 (−) N-(1-(Z)-Octadec-9- enoyloxy)ethoxycarbonyl)-(−)-N-ethyl-3- phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P5-009 (−) N-(1- Tetradecanoyloxy- ethoxycarbonyl)- (−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P5-010 (−) N-(1- Hexadecanoyloxy- ethoxycarbonyl)- (−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P5-011 (+) N-(1- Octadecanoyloxy- ethoxycarbonyl)- (+)-N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P6-001 (−) N-(Glycyl-glycyl)-(−)- N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P6-002 (−) N-(Valyl-D-valyl)-(−)- N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P6-003 N-(Glycyl-Alanyl)-(−)- N-ethyl-3- phenylbicyclo[2.2.1]heptan-2-amine

PRX-P6-004 (−) N-(Valyl-valyl)-(−)- N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P6-005 (−) N-(Phenylalanyl- phenylalanyl-(−)- N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P6-006 (−) N-(Alanyl-glycyl)-(−)- N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P6-007 (−) N-(N6-Lysyl-lysyl)-(−)- N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

PRX-P6-011 (+) N-(Valyl-valyl)-(+)- N-ethyl-3-phenylbicyclo[2.2.1]heptan- 2-amine

EXAMPLES Preparation of Compounds of Formula (I) Example 1. PRX-001(Exo-phenyl,endo-amino)-N-Ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(also known as N-Ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-amine)

Fencamfamine((Exo-phenyl,endo-amino)-N-Ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine,PRX-001) was synthesized according to the scheme 1 and modifications ofthe methods described in Pharmaceutical Chemistry Journal 2011, 45(7),419-422, Journal of Organic Chemistry 1961, 26, 5247-5249, GB 913866,Organometallics, 2013, 32, 1609-1619, and Organic Letters 2007, 9, 2819,

Step 1. Cyclopenta-1,3-Diene (I-1)

The synthesis of the intermediate was performed as described in OrganicSyntheses, Coll. Vol. 4, p. 238 (1963); Vol. 32, p. 41 (1952).

Dicyclopentadiene (500 g) was added to a 1 L two-necked round-bottomedflask equipped with thermometer and an upright Friedrich's-typecondenser (through which water at 50° C. was circulated). Theground-glass outlet of the Friedrich's condenser was connected to theside arm of a simple distilling head fitted with a thermometer andattached to an efficient water-cooled condenser held in a verticalposition. At the lower end of this condenser, a receiver was attachedwhich consisted of a weighed 500-ml, two-necked round-bottomed flaskimmersed in a Dry Ice bath and protected from the air by a calciumchloride drying tube.

The flask containing dicyclopentadiene was heated by means of oil bathuntil cyclopentadiene distilled (approximately 160-170° C.) into thereceiver which was placed in dry ice cooling bath. After two-third ofthe dicyclopentadiene had been pyrolyzed during the course of 4-5 hours,the residue in the flask may tend to become viscous and a highertemperature for pyrolysis will be required in order to obtain rapiddistillation of cyclopentadiene in such case it was desirable to discardthe residue while it was still hot and mobile. The distilledcyclopentadiene (I-1) (200 g, 40%) was obtained as a colorless liquidand which was taken for next step immediately to avoid dimerization.

Step 2. 5-Nitro-6-Phenyl-Bicyclo[2.2.1]Hept-2-Ene (I-2A and I-2B)

To a stirred solution of 6-Nitro styrene (500 g, 3.352 mol) indichloroethane (1 L) was added freshly distilled cyclopentadiene (I-1)(800 mL) and pale yellow colored reaction mixture was stirred for 12 hunder argon atmosphere at 70° C. After the completion of reaction (TLCeluent: 5% EtOAc in petroleum ether), the reaction mixture wasconcentrated under reduced pressure. The residue thus obtained waspurified by column chromatography over 60-120 silica gel (4.5 Kg) using1% EtOAc in petroleum ether to afford the mixture of intermediates I-2aand I-2b as a thick pale yellow colored liquid (680 g, 94%).

¹H-NMR (CDCl₃, 400 MHz) δ 7.39-7.19 (m, 5H), 6.63-6.61 (dd, J=3.2 Hz &5.6 Hz, 1H), 6.15-6.13 (m, 1H), 5.03-5.01 (t, J=4 Hz, 1H), 3.63-3.62 (m,1H), 3.50-3.46 (d, J=4 Hz, 1H), 3.20-3.19 (d, J=1.6 Hz, 1H), 1.92-1.89(m, 1H), 1.78-1.74 (m, 1H).

Step 3. (Exo-Phenyl,Endo-Amino)-3-Phenylbicyclo[2.2.1]Heptan-2-Amine(I-3A)

In an autoclave hydrogenation apparatus, to the solution of the mixtureof I-2a and I-2b (600 g, 2.787 mol) in methanol (6 L) was added 10% Pd/C(120 g) and the reaction mixture was stirred for 32 hours under H₂pressure of 5 Kg/m². The reaction was monitored by TLC (TLC eluent: 5%MeOH in CH₂Cl₂). After the completion of reaction, the reaction mixturewas filtered through Celite and the filtrate was concentrated underreduced pressure to give an 80:20 mixture of the (Exo-phenyl,endo-amino)and (Endo-phenyl,exo-amino) isomers with Rf values of 0.35 and 0.2,respectively (CH2Cl2-MeOH, 90:10, eluted twice). The crude residueobtained was purified by chromatography on silica gel (15×60 cm, 230-400mesh) using 1.5% methanolic ammonia in dichloromethane as eluent andrechromatographed on the same column to give intermediate I-3a as athick pale yellow colored liquid (280 g, 54% yield).

¹H-NMR (DMSO, 400 MHz) δ 7.26-7.23 (m, 4H), 7.16-7.12 (m, 1H), 3.05-3.02(m, 1H), 2.22-2.21 (d, J=3.6 Hz, 1H), 2.06-2.05 (m, 1H), 1.98-1.96 (dd,J=2 Hz & 5.6 Hz, 1H), 1.89-1.83 (m, 1H), 1.65-1.51 (m, 4H), 1.37-1.26(m, 3H).

[M+H]⁺=188.1; HPLC Purity: 94.6%.

Step 4. (Exo-Phenyl,Endo-Amino)-N-Acetyl-3-Phenylbicyclo[2.2.1]Heptan-2-Amine (I-4)

To a solution of I-3a (50 g, 0.266 mol) in CH₂Cl₂ (350 mL) was addedtriethylamine (75 mL, 0.533 mol) at ambient temperature. After 10 minstirring, acetyl chloride (23 mL, 0.320 mol) was added dropwise at 0° C.and stirring was continued further for a period of 1 h. After thecompletion of reaction, reaction mixture was quenched with water (500mL) and the product was extracted with DCM (2×200 mL). The organic layerwas treated with 1.5N HCl (2×100 mL), sat.NaHCO₃ (2×100 mL), brine(2×100 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford yellow crude semi solid intermediate 6. Further itwas triturated with diethyl ether (10×500 mL) to obtain 1-4 as a pureoff white solid (47 g, 82% yield), mp 159-161° C.

¹H NMR (CDCl₃, 400 MHz) δ 7.31-7.24 (m, 4H), 7.21-7.18 (m, 1H), 5.68 (s,1H), 4.35-4.32 (m, 1H), 2.61 (s, 1H), 2.40-2.39 (d, J=3.2 Hz, 1H),2.22-2.21 (d, J=4.8 Hz, 1H), 2.0 (s, 3H), 1.87-1.64 (m, 2H), 1.57-1.51(m, 2H), 1.45-1.35 (m, 2H).

[M+H]⁺=230.3, HPLC purity: 98.5%

Step 5: (Exo-Phenyl,Endo-Amino)-N-Ethyl-3-Phenylbicyclo[2.2.1]Heptan-2-Amine (PRX-001)

To a stirred suspension of lithium aluminum hydride (30 g, 0.348 mol) indry THF (200 mL) was added dropwise a solution of I-4 (40 g, 0.174 mol)dry THF (200 mL) at 0° C. After addition, the reaction mixture wasrefluxed at 70° C. for 16 h under argon atmosphere. After the completionof the reaction (TLC eluent: 70% EtOAc in petroleum ether), the reactionmixture was added dropwise to an ice cold solution of 4N NaOH (2 L)solution with stirring. After complete quenching, it was filteredthrough Celite. The filtrate was extracted with EtOAc (3×400 mL) andwashed with brine (2×200 mL). The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure to obtain crudePRX-001, (33 g) as a pale yellow liquid.

To a solution of crude PRX-001 (33 g) in diethyl ether (66 mL) was addedethereal HCl (130 mL) at 0° C. After 1 h, the off-white precipitate. wascollected, washed with excess of diethyl ether and dried under vacuum.The obtained solid was dissolved in EtOAc (200 mL), basified with 2NNaOH solution. The separated organic layer was treated with brine (2×100mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain PRX-001 as a pure pale yellow liquid (30 g, 81%yield).

¹H-NMR (CDCl₃, 400 MHz) δ 7.30-7.28 (m, 4H), 7.21-7.17 (m, 1H),3.17-3.14 (m, 1H), 2.59-2.49 (q, 2H), 2.42 (s, 1H), 2.26-2.25 (d, J=4Hz, 1H), 2.16-2.15 (m, 1H), 1.79-1.74 (m, 2H), 1.68-1.59 (m, 3H),1.47-1.38 (m, 2H), 1.09 (t, 3H).

[M+H]+=216.0; HPLC purity: 94.3%

Example 2: (+)- and(−)-(Exo-Phenyl,Endo-Amino)-N-Ethyl-3-Phenylbicyclo[2.2.1]Heptan-2-Amine,(+)-PRX-002 and (−)-PRX-002 (Also Known as.N-Ethyl-(3-Phenyl-Bicyclo[2.2.1]Hept-2-yl)-Amine)

Racemic PRX-001 (90 g in 200 mg batches) was resolved by chiralpreparative HPLC on a Chiralpak AD column (250×50 mm) eluted with 0.1%diethylamine in isopropanol (43 mL/min) to afford the two enantiomers,(+)-PRX-002 (37 g), and (−)-PRX-002 (39 g).

PRX-002 (+ isomer): 1H-NMR (CDCl3, 400 MHz) δ 7.30-7.27 (m, 4H),7.21-7.17 (m, 1H), 3.17-3.15 (m, 1H), 2.59 (q, 2H), 2.42 (s, 1H),2.27-2.26 (d, J=4 Hz, 1H), 2.16-2.15 (dd, J=2 Hz & 5.6 Hz, 1H),1.77-1.74 (m, 2H), 1.65-1.61 (m, 1H), 1.48-1.41 (m, 3H), 1.36-1.32 (m,1H), 1.06 (t, 3H).

[M+H]+=216.3;

HPLC Retention Time (min)=4.42, purity 97.7%

Chiral HPLC Retention Time (min) 12.63, purity 99.6%

[α]20 D: +52.76° (sample concentration: 0.16% in MeOH)

PRX-002 (− isomer): ¹H-NMR (CDCl₃, 400 MHz) δ 7.30-7.27 (m, 4H),7.21-7.17 (m, 1H), 3.17-3.15 (m, 1H), 2.59 (q, 2H), 2.42 (s, 1H),2.27-2.26 (d, J=4 Hz, 1H), 2.16-2.15 (dd, J=2 Hz & 5.6 Hz, 1H),1.77-1.74 (m, 2H), 1.65-1.61 (m, 1H), 1.48-1.41 (m, 3H), 1.36-1.32 (m,1H), 1.06 (t, 3H).

[M+H]+=216.3

HPLC Ret. Time (min) 4.426, purity 95.5%

Chiral HPLC Ret. Time (min) 14.437, purity 97.3%

[α]20D: −49.70° (sample concentration: 0.17% in MeOH)

The HCl salt of (+)-PRX-002 (120 mg) was dissolved in warm methanol (0.1mL) and water (0.2 mL), then allowed to cool to room temperature. Aresulting rectangular crystal was analyzed by X-ray crystallographywhich indicated the absolute configuration indicated in Scheme 1 for(+)-fencamfamine. The structures presented herein are from the samecompounds as initially tested in the examples, updated after X-raycrystallography was performed.

Example 3. PRX-P1-001N-Succinyl-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine (Also Known asN-Ethyl-N-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-succinamic Acid)

To a stirred solution of mono methyl succinate (0.92 g, 6.96 mmol) inDMF (10 mL, 10 volumes) was added EDC.HCl (1.33 g, 6.96 mmol), HOBT(0.94 g, 6.96 mmol) and triethylamine (1.29 mL, 9.28 mmol) at ambienttemperature. After 10 min, N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(PRX-001) (1 g, 4.64 mmol) dissolved in DMF (2 mL, 2 volumes) was addeddropwise and reaction mixture was further stirred for 12 h at ambienttemperature. After the completion of reaction (TLC eluent: 70% EtOAc inpetroleum ether), the reaction mixture was quenched with water (200 mL)and product was extracted with EtOAc (2×50 mL). The combined organiclayer was washed with brine solution (50 mL), dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue thusobtained was purified by flash column chromatography with silica gel60-120 mesh (12% EtOAc in petroleum ether) to obtain 1-5 (1.14 g, 75%).

To a stirred solution of I-5 (0.85 g, 2.60 mmol) in a mixture of THF andMeOH (1:1, 20 mL) was added LiOH (0.32 g, 7.80 mmol) in water at 0° C.and reaction mixture was stirred for 1 hour. After the completion ofreaction (70% EtOAc in petroleum ether), the reaction mixture wastreated with 10% aqueous ammonium chloride solution (100 mL), extractedwith EtOAc (2×50 mL). The combined organic layer was washed with brine(30 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue thus obtained was purified by flash columnchromatography over silica gel 60-120 mesh using 2% of MeOH indichloromethane to obtain (PRX-P1-001) as a sticky off white solid (0.57g, 70%).

¹H-NMR (CDCl₃, 400 MHz) δ 7.31-7.19 (m, 5H), 4.74 (s, 1H), 4.15 (s, 1H),3.99-3.96 (m, 1H), 3.63-3.55 (m, 1H), 3.39-3.37 (m, 1H), 3.18-3.13 (m,1H), 2.90-2.42 (m, 4H), 1.84-1.67 (m, 4H), 1.54-1.50 (m, 2H), 1.37 (t,J=6.7 Hz, 3H).

[M−H]⁻=314.0

Example 4. General Synthetic Procedure for PRX-P1-005, PRX-P1-006,PRX-P1-012, and PRX-P1-013

Step 1: To a solution of N-Boc protected amino acids (1.2 eq) in DMF (5volumes) was added HATU (1.5 eq), Et₃N (2 eq) and stirred the reactionmixture for 20 min. Then, PRX-002 (+) isomer or (−) isomer (1 eq) in DMF(5 volumes) was added dropwise and the reaction was continued for 12hour at ambient temperature. After the completion of reaction (TLCeluent: 40% EtOAc in petroleum ether), the reaction product was treatedwith ice cold water (20 volumes) and product was extracted with ethylacetate (2×10 volumes). The combined organic layer was washed with 3%citric acid solution (2×10 volumes), saturated NaHCO₃ solution (2×10volumes) and brine solution (1 volume). The obtained organic layer wasdried over anhydrous sodium sulfate, concentrated under reducedpressure. The crude product thus obtained was purified by using flashcolumn chromatography to obtain intermediate I-6.

Step 2: To a solution of I-6 (1 eq) in DCM (5 volumes) was added TFA (1volume) dropwise at 0-5° C. and after complete addition, reactionmixture was stirred for 30 min at ambient temperature. After thecompletion of reaction (TLC eluent: 80% EtOAc in n-hexane), the solventwas concentrated under reduced pressure. The residue thus obtained waswashed with n-hexane (2×20 volumes) for removal of impurities. Then itwas dissolved in ethyl acetate (2×20 volumes), neutralized withsaturated NaHCO₃ solution (20 volumes) and washed with brine solution(20 volumes). After separation, the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford amino acid bonded prodrugs, including compounds PRX-P1-005,PRX-P1-006, PRX-P1-012, and PRX-P1-013.

Example 5. PRX-P1-006N-Valyl-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine (Also Known as(S)-2-amino-N-ethyl-3-methyl-N-(3-phenylbicyclo[2.2.1]heptan-2-yl)butanamide)

Using the general procedure described in Example 4 above employingPRX-001 (±) isomers, (500 mg, 2.32 mmol) and(S)-2-(Boc-amino)-3-methylbutyric acid (504 mg, 2.32 mmol), provided theproduct (PRX-P1-006) (460 mg, 64% yield) as a brownish liquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.33-7.18 (m, 5H), 4.80-4.78 (m, 1H), 4.51 (s,1H), 4.14 (s, 1H), 3.61-3.31 (m, 1H), 3.09-3.08 (m, 1H), 2.97-2.91 (m,1H), 2.50-2.41 (m, 2H), 3.00-2.90 (m, 2H), 2.71-2.66 (m, 1H), 2.44-2.28(m, 2H), 1.66-1.61 (m, 2H), 1.42-1.36 (m, 1H), 1.26-1.19 (m, 6H), 1.01(t, J=5.6 Hz, 3H)

[M+H]⁺=315.4

Example 6. PRX-P1-005N-Lysyl-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine (Also Known as(S)-2,6-diamino-N-ethyl-N-(3-phenylbicyclo[2.2.1]heptan-2-yl)hexanamide)

Using the general procedure described in Example 4 above employingPRX-002 (−) isomer, (200 mg, 0.92 mmol) and(S)-2,6-bis-tert-butoxycarbonylamino-hexanoic acid (386 mg, 1.11 mmol),provided the product (PRX-P1-005) (160 mg, 160 mg % yield) as a paleyellow liquid.

¹H-NMR (DMSO, 400 MHz) δ 8.34 (s, 2H), 7.33-7.18 (m, 5H), 4.60 (s, 1H),4.38 (s, 1H), 4.06 (s, 1H), 3.82-3.78 (m, 1H), 3.64-3.35 (m, 4H),3.33-3.29 (m, 2H), 3.00-2.90 (m, 2H), 2.71-2.66 (m, 1H), 2.44-2.28 (m,2H), 1.66-1.61 (m, 2H), 1.50-1.45 (m, 2H), 1.42-1.36 (m, 2H), 1.26-1.19(m, 2H), 1.01 (t, J=5.6 Hz, 3H) [M+H]⁺=344.5

Example 7. PRX-P1-012N-Glycyl-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine (Also Known as2-Amino-N-ethyl-N-(3-phenyl-bicyclo [2.2.1]hept-2-yl)-acetamide)

Using the general procedure described in Example 4 above employingPRX-002 (−) isomer, (500 mg, 2.32 mmol) andN-(tert-butoxycarbonyl)glycine (487 mg, 2.78 mmol), provided the product(PRX-P1-012) (420 mg, 68% yield) as a yellow liquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.38-7.25 (m, 4H), 7.23-7.11 (m, 1H),4.58-4.57 (m, 1H), 4.42-4.40 (m, 1H), 3.32-3.21 (m, 1H), 2.93-2.92 (m,1H), 2.32-2.31 (m, 1H), 1.66-1.57 (m, 5H), 1.48-1.40 (m, 2H), 1.23-1.18(m, 2H), 1.00 (t, J=5.6 Hz, 3H)

[M+H]⁺=273.3

Example 8. PRX-P1-013N-Phenylalanyl-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine (AlsoKnown as (S)-2-Amino-N-ethyl-3-phenyl-N-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-propionamide)

Using the general procedure described in Example 4 above employingPRX-002 (−) isomer, (0.7 g, 3.25 mmol) andN-(tert-butoxycarbonyl)-L-phenylalanine (1 g, 3.90 mmol), provided theproduct (PRX-P1-013), (0.73 g, 62% yield as a yellow liquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.26-6.99 (m, 10H), 4.80-4.78 (m, 1H),4.67-4.56 (m, 1H), 4.05-4.00 (m, 1H), 3.61-3.11 (m, 2H), 3.09-2.80 (m,5H), 2.50-2.41 (m, 2H), 1.66-1.61 (m, 1H), 1.42-1.36 (m, 1H), 1.26-1.19(m, 1H), 1.01 (t, J=5.6 Hz, 3H)

[M+H]⁺=363.1

Example 9. PRX-P2-001N-Ethoxycarbonyl-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine (AlsoKnown as Ethyl N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-yl)carbamate)

To a solution of PRX-001 (200 mg, 0.93 mmol in DCM (2 mL, 10 volumes)was added Et₃N (0.25 mL, 1.86 mmol) and reaction mixture was cooled to0° C. After 5 minutes stirring, ethyl chloroformate (0.1 mL, 1.11 mmol)was added dropwise and then the reaction mixture was stirred at ambienttemperature for 16 hours. After the completion of reaction (TLC eluent:60% EtOAc in petroleum ether), the reaction mixture was concentrated todryness and then dissolved in ethyl acetate (50 mL), washed with water(2×20 mL) and brine solution (20 mL). The organic layer was dried overanhydrous sodium sulfate, concentrated under reduced pressure. The crudeproduct obtained was purified by flash column chromatography with silica(60-120) mesh using 10-12% EtOAc in hexane as eluent to obtain theproduct (PRX-P2-001) as pale yellow liquid (106 mg, 40%).

1H-NMR (CDCl₃, 400 MHz) δ 7.33-7.27 (m, 4H), 7.22-7.17 (m, 1H),4.39-4.37 (m, 1H), 4.19-4.09 (m, 2H), 3.69-3.56 (m, 1H), 3.25-3.17 (m,1H), 2.86-2.85 (d, J=6 Hz, 1H), 2.60 (s, 1H), 2.44-2.43 (d, J=3.2 Hz,1H), 1.77-1.63 (m, 2H), 1.54-1.43 (m, 3H) 1.29-1.23 (m, 4H), 1.10 (t,J=7.2 Hz, 3H)

[M+H]⁺=288.4

Example 10. General Synthetic Procedure for PRX-P3-002 and PRX-P3-004

Step 1: To a stirred solution of triphosgene (0.5 eq) in THF (5 volumes)at 0° C., was added dropwise a solution of phenol derivative (1 eq) andDIPEA (1 eq) in THF (5 volumes) and the reaction mixture was kept atambient temperature for 12 hours. After the completion of reaction (TLCeluent: 10% EtOAc in hexane), the reaction mixture was treated withwater (20 volumes) and product was extracted with EtOAc (2×20 volumes).The combined organic layer were dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to obtain crudeintermediate I-7, which was carried forwarded for the next step.

Step 2: To a stirred solution of (−)-PRX-002 (1 eq) in dry THF (5volumes), were added DMAP (0.1 eq) and Et₃N (2 eq). The mixture wasstirred for 10 min at ambient temperature. Then a solution of I-7 (2 eq)in THF (5 volumes) was added dropwise and the reaction mixture wasstirred for 12 hours at ambient temperature and monitored TLC (eluent:5% EtOAc in hexane). Then, the reaction mixture was treated with water(20 volumes), and extracted with EtOAc (2×30 volumes). The organic layerwas washed with brine (20 volumes), dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue thus obtained waspurified by preparative HPLC method to afford aryl carbamate linkedprodrug, including Compounds PRX-P3-002 and PRX-P3-004. For the presentexample, R denotes the atoms for the noted compounds PRX-P3-002 andPRX-P3-004.

Example 11. (PRX-P3-002)N-(5-Isopropyl-2-methylphenoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as 5-isopropyl-2-methylphenylN-ethyl-(3-phenylbicyclo[2.2.1]heptan-2-yl)carbamate)

Using the general procedure described in Example 10 above employingPRX-002 (−) isomer, (250 mg, 1.17 mmol) and carvacrol (400 mg, 2.66mmol), provided the product (PRX-P3-002) (337 mg, 75% yield) as acolorless liquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.34-7.30 (m, 4H), 7.24-7.21 (m, 1H),7.13-7.11 (d, J=8 Hz, 1H), 6.99-6.96 (m, 1H), 6.91 (s, 1H), 4.49 (s,1H), 3.76-3.71 (m, 1H), 3.40-3.35 (m, 1H), 2.99 (s, 1H), 2.90-2.84 (m,1H), 2.74 (s, 1H), 2.48 (s, 1H), 2.14 (s, 3H), 1.81-1.70 (m, 3H),1.60-1.52 (m, 2H), 1.31-1.19 (m, 10H).

[M+H]⁺=392.2

Example 12. PRX-P3-004N-(2-Isopropyl-5-methylphenoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as 2-Isopropyl-5-methylphenylN-ethyl-(3-phenylbicyclo[2.2.1]heptan-2-yl)carbamate)

Using the general procedure described in Example 10 above employingPRX-002 (−) isomer, (250 mg, 1.17 mmol) and thymol (400 mg, 2.66 mmol),provided the product (PRX-P3-004) (351 mg, 78% yield) as a transparentliquid.

¹H NMR (CDCl₃, 400 MHz) δ 7.34-7.33 (m, 4H), 7.23-7.22 (m, 1H), 7.17 (d,J=7.6 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 6.87 (s, 1H), 4.49 (s, 1H),3.75-3.70 (m, 1H), 3.38 (s, 2H), 3.00 (s, 2H), 2.71 (s, 1H), 2.49 (s,1H), 2.31 (s, 3H), 1.81-1.70 (m, 3H), 1.56-1.55 (m, 1H), 1.31-1.17 (m,10H).

[M+H]⁺=392.2

Example 13. General Synthetic Procedure for PRX-P4-002, PRX-P4-005, andPRX-P4-004

Step 1: To a solution of N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(PRX-002) (1 eq) in dichloromethane (10 volumes) under argon atmosphere,was added triethylamine (2 eq) dropwise at ambient temperature and themixture was stirred for 5 min. Then, chloromethyl chloroformate (1.5 eq)was introduced dropwise at 0-5° C. and the reaction mixture was furtherstirred at ambient temperature for 30 min. After the completion ofreaction (TLC eluent: 20% EtOAc in petroleum ether), the reactionmixture was quenched in water (20 volumes), extracted withdichloromethane (2×20 volumes). The combined organic layer was washedwith water (2×20 volumes), brine (20×1 volumes) solution, filtered,dried over anhydrous sodium sulfate and concentrated under reducedpressure to obtainN-(Chloromethoxycarbonyl)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(I-8) as a thick brown liquid, which was used in the next step withoutfurther purification.

Step 2: To a solution ofN-(Chloromethoxycarbonyl)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(also known as ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamic acidchloromethyl ester) (I-8) (1 eq) in DMF (10 volumes) was added dryCs₂CO₃ (2 eq), acid (R—COOH) (2 eq), and 1<1 (0.2 eq) at ambienttemperature. The reaction mixture was heated to 100-105° C. and stirredfor 4 h. After completion of reaction (TLC eluent: 10% EtOAc inn-hexane), the reaction mixture was quenched in water (20 volumes),extracted with ethyl acetate (2×20 volumes). Combined organic layer waswashed with water (2×10 volumes), brine solution (10 volumes), filtered,dried over anhydrous sodium sulfate and concentrated under reducedpressure. The crude residue obtained was purified by flash columnchromatography or preparative HPLC to yield acyloxymethoxycarbonylpro-drugs of PRX-002, including PRX-P4-002, PRX-P4-005, and PRX-P4-004.For the present example, R denotes the atoms for the noted compoundsPRX-P4-002, PRX-P4-005, and PRX-P4-004.

Example 14. PRX-P4-001N-(Acetoxymethoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(also known as((N-ethyl-(3-phenylbicyclo[2.2.1]heptan-2-yl)carbamoyl)oxy)methylAcetate)

Using the general procedure described in Example 14 above employingPRX-002 (−) isomer, (200 mg, 0.92 mmol) and sodium acetate (160 mg,1.9493 mmol), provided the product (PRX-P4-001) (132 mg, 44% yield) as acolorless liquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.31-7.27 (m, 4H), 7.22-7.21 (m, 1H), 5.80(dd, J=5.6 & 11.6 Hz, 1H), 4.39-4.37 (m, 1H), 3.59 (brs, 1H), 3.27-3.18(m, 1H), 2.89 (d, J=5.2 Hz, 1H), 2.61 (s, 1H), 2.43 (d, J=3.2 Hz, 1H),2.12 (s, 3H), 1.75-1.70 (m, 2H), 1.61-1.59 (m, 1H), 1.55-1.45 (m, 3H),1.28-1.25 (m, 1H), 1.10 (t, J=6.8 Hz, 3H)

[M+Na]⁺=354.20

Example 15. PRX-P4-002N-(Decanoyloxymethoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as(N-ethyl-(3-phenylbicyclo[2.2.1]heptan-2-yl)carbamoyl)oxy)methyldecanoate (− Isomer))

Using the general procedure described in Example 14 above employingPRX-002 (−) isomer, (1.5 g, 6.96 mmol) and Decanoic acid (1.76 g, 10.23mmol), provided the product (PRX-P4-002) (1.23 g, 40% yield) as a thicktransparent liquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.33-7.27 (m, 4H), 7.22-7.18 (m, 1H), 5.87(dd, J=5.6 & 10.8 Hz, 1H), 4.38-4.35 (m, 1H), 3.59 (brs, 1H), 3.27-3.17(m, 1H), 2.89-2.88 (d, J=5.2 Hz, 1H), 2.61 (s, 1H), 2.43 (d, J=3.2 Hz,1H), 2.37-2.32 (m, 2H), 1.78-1.71 (m, 2H), 1.70-1.58 (m, 3H), 1.57-1.42(m, 1H), 1.29-1.25 (m, 15H), 1.09 (t, J=6.8 Hz, 3H), 0.90 (t, J=6.4 Hz,3H). [M+Na]⁺=466.30

Example 16. Compound 15 (PRX-P4-003)N-(Octadecanoyloxymethoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as((N-Ethyl-(3-phenylbicyclo[2.2.1]heptan-2-yl)carbamoyl)oxy)methylOctadecanoate)

Using the general procedure described in Example 14 above employingPRX-002 (−) isomer, (5 g, 23.21 mmol) and octadecanoic acid (9.7 g,34.11 mmol), provided the product (PRX-P4-003) (4.9 g, 38% yield) as acolorless liquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.31-7.27 (m, 4H), 7.22-7.18 (m, 1H), 5.80(dd, J=5.6 & 10.8 Hz, 1H), 4.38-4.36 (m, 1H), 3.59 (brs, 1H), 3.26-3.18(m, 1H), 2.90 (d, J=5.6 Hz, 1H), 2.61 (s, 1H), 2.43 (d, J=3.6 Hz, 1H),2.36-2.32 (m, 2H), 1.75-1.71 (m, 2H), 1.63-1.50 (m, 5H), 1.30-1.25 (m,30H), 1.09 (t, J=6.8 Hz, 3H), 0.90 (t, J=6.4 Hz, 3H)

[M+Na]⁺=578.4

Example 17. PRX-P4-004N—((Z)-Octadec-9-enoyloxymethoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as (Z)-Octadec-9-enoic acid[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyloxy]-methyl Ester)

Using the general procedure described in Example 14 above employingPRX-002 (−) isomer, (1 g, 4.64 mmol) and oleic acid (2.56 g, 9.09 mmol),provided the product (PRX-P4-004) (0.91 g, 30% yield) as a colorlessliquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.33-7.27 (m, 4H), 7.22-7.18 (m, 1H), 5.80(dd, J=5.6 & 10.8 Hz, 2H), 5.39-5.30 (m, 2H), 4.38-4.37 (m, 1H), 3.59(brs, 1H), 3.26-3.17 (m, 1H), 2.90 (d, J=5.6 Hz, 1H), 2.61 (s, 1H), 2.43(d, J=3.6 Hz, 1H), 2.34 (t, J=7.6 Hz, 2H), 2.01-1.98 (m, 3H), 1.78-1.74(m, 2H), 1.63-1.51 (m, 4H), 1.28-1.25 (m, 23H), 1.09 (t, J=6.8 Hz, 3H),0.90 (t, J=6.8 Hz, 3H) [M+H]⁺=554.4

Example 18. General Synthetic Procedure for PRX-P5-001 to PRX-P5-011

Step 1: To a solution of N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine,PRX-002 (+) isomer or (−) isomer, (1 eq) in DCM (10 volumes) under argonatmosphere, was added triethylamine (2 eq) dropwise at ambienttemperature. After stirring for 5 minutes, 1-chloroethyl chloroformate(2) (1.5 eq) was added dropwise at 0-5° C. and the reaction mixture wasfurther stirred at ambient temperature for 30 min. After the completionof reaction (TLC eluent: 20% EtOAc in petroleum ether) the reactionmixture was quenched in water (20 volumes), extracted with DCM (2×20volumes). The combined organic layer was washed with water and brine,dried over anhydrous sodium sulfate and concentrated under reducedpressure to obtainN-(1-Chloroethoxycarbonyl)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(I-9) as a thick brown liquid, which was carried forwarded for the nextstep without purification.

Step 2: To a solution of intermediate I-9 (1 eq) in DMF (10 volumes) wasadded dry Cs₂CO₃ (2 eq), a fatty acid (R—COOH) (2 eq), and KI (0.2 eq)at ambient temperature and the reaction mixture was heated at 100-105°C. and stirred for 4 hours. After completion of reaction (TLC eluent:10% EtOAc in n-Hexane), the reaction mixture was quenched in water (20volumes), extracted with ethyl acetate (2×20 volumes). Combined organiclayer was washed with water (2×10 volumes) and brine solution (10volumes), further dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The crude residue obtained was purified byeither flash column chromatography/preparative HPLC to yield1-Acyloxyethoxycarbonyl pro-drugs, including Compounds PRX-P5-001 toPRX-P5-011.

Example 19. PRX-P5-001)N-(1-Acetoxyethoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as Acetic acid1-[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyloxy]-ethyl Ester)

Using the general procedure described in Example 18 above employingPRX-002 (−) isomer, (200 mg, 0.92 mmol) and sodium acetate (152 mg, 1.86mmol), provided a the product (PRX-P5-001) (89 mg, 28% yield) as a paleyellow liquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.33-7.27 (m, 4H), 7.23-7.19 (m, 1H), 6.87 (q,1H), 4.35-4.33 (m, 1H), 3.59-3.56 (m, 1H), 3.25-3.18 (m, 1H), 2.88-2.87(d, J=5.6 Hz, 1H), 2.62 (s, 1H), 2.44-2.42 (m, 1H), 2.07 (s, 3H),1.75-1.69 (m, 2H), 1.61-1.55 (m, 7H), 1.10 (t, J=7.2 Hz, 3H).

[M+Na]⁺=368.2

Example 20. PRX-P5-002N-(1-Decanoyloxyethoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as Decanoic acid1-[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyloxy]-ethyl Ester)

Using the general procedure described in Example 18 above employingPRX-002 (−) isomer, (300 mg, 1.39 mmol) and decanoic acid (482 mg, 2.80mmol), provided the product (PRX-P5-002) (242 mg, 38% yield) as a paleyellow liquid:

¹H-NMR (CDCl₃, 400 MHz) δ 7.33-7.27 (m, 4H), 7.22-7.18 (m, 1H),6.87-6.83 (q, J=5.2 Hz, 1H), 4.35-4.32 (m, 1H), 3.58-3.54 (m, 1H),3.25-3.18 (m, 1H), 2.89-2.88 (d, J=6 Hz, 1H), 2.61 (s, 1H), 2.44-2.43(m, 1H), 2.32-2.27 (m, 2H), 1.75-1.68 (m, 2H), 1.64-1.59 (m, 4H),1.56-1.42 (m, 5H), 1.34-1.26 (m, 10H), 1.10 (t, J=6.8 Hz, 3H), 0.90 (m,5H)

[M+Na]⁺=480.3

Example 21. PRX-P5-003N-(1-Butanoyloxyethoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as Butyric Acid1-[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyloxy]-ethyl Ester)

Using the general procedure described in Example 18 above employingPRX-002 (−) isomer, (330 mg, 1.55 mmol) and butanoic acid (274 mg, 3.10mmol), provided the product (PRX-P5-003) (240 mg, 42% yield) as a yellowliquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.35-7.27 (m, 4H), 7.24-7.18 (m, 1H), 6.88 (q,1H), 4.35 (s, 1H), 3.67-3.40 (m, 1H), 3.39-3.06 (m, 1H), 2.89 (d, J=6Hz, 1H), 2.61 (s, 1H), 2.44-2.43 (m, 1H), 2.32-2.27 (m, 2H), 1.75-1.47(m, 9H), 1.34-1.24 (m, 2H), 1.10 (t, J=6.8 Hz, 3H), 0.90 (t, 3H)

[M+Na]⁺=396.4

Example 22. PRX-P5-004N-(1-Octanoyloxyethoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as Octanoic Acid1-[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyloxy]-ethyl Ester)

Using the general procedure described in Example 18 above employingPRX-002 (−) isomer, (330 mg, 1.55 mmol) and octanoic acid (447 mg, 3.10mmol), provided the product (PRX-P5-004) (184 mg, 28% yield) as a yellowliquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.33-7.27 (m, 4H), 7.22-7.18 (m, 1H),6.87-6.83 (q, J=5.6 Hz, 1H), 4.35 (d, J=5.6 Hz, 1H), 3.57-3.56 (m, 1H),3.24-3.17 (m, 1H), 2.89 (d, J=8 Hz, 1H), 2.61 (s, 1H), 2.44-2.43 (m,1H), 2.32-2.27 (m, 2H), 1.75-1.68 (m, 4H), 1.53-1.45 (m, 4H), 1.28-1.26(m, 11H), 1.09 (t, J=6.8 Hz, 3H), 0.89 (t, 3H)

[M+Na]⁺=452.60

Example 23. PRX-P5-005N-(1-Dodecanoyloxyethoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as Dodecanoic acid 1-[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyloxy]-ethyl Ester)

Using the general procedure described in Example 18 above employingPRX-002 (−) isomer, (330 mg, 1.55 mmol) and dodecanoic acid (622 mg,3.10 mmol), provided the product (PRX-P5-005) (300 mg, 40% yield) as ayellow liquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.33-7.27 (m, 4H), 7.22-7.20 (m, 1H), 6.87 (q,J=5.6 Hz, 1H), 4.35-4.33 (m, 1H), 3.23-3.21 (m, 1H), 2.89 (d, J=6 Hz,1H), 2.61 (s, 1H), 2.44-2.43 (m, 1H), 2.32-2.27 (m, 2H), 1.87-1.78 (m,2H), 1.67-1.55 (m, 8H), 1.54-1.52 (m, 5H), 1.35-1.30 (m, 10H), 1.29 (t,3H), 0.90-0.89 (m, 6H) [M+Na]⁺=508.6

Example 24. PRX-P5-006N-(1-Octadecanoyloxyethoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as Octadecanoic Acid1-[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyloxy]-ethyl Ester)

Using the general procedure described in Example 18 above employingPRX-002 (−) isomer, (5 g, 23.22 mmol) and octadecanoic acid (13.27 g,46.68 mmol), provided the product (PRX-P5-006) (5.82 g, 44% yield) as apale yellow liquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.33-7.27 (m, 4H), 7.22-7.18 (m, 1H), 6.87 (q,J=5.6 Hz, 1H), 4.35 (d, J=6 Hz, 1H), 3.57 (d, J=5.2 Hz, 1H), 3.26-3.18(m, 1H), 2.89 (d, J=6 Hz, 1H), 2.61 (s, 1H), 2.44 (S, 1H), 2.33-2.27 (m,2H), 1.76-1.68 (m, 2H), 1.64-1.56 (m, 4H), 1.54-1.47 (m, 5H), 1.42-1.26(m, 23H), 1.13-1.06 (m, 5H), 0.90-0.84 (m, 6H)

[M+Na]⁺=592.70

Example 25. PRX-P5-007N-(1-(2,2-Dimethylpropionyloxy)ethoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(also known as 2,2-Dimethyl-propionic acid 1-[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyloxy]-ethyl Ester)

Using the general procedure described in Example 18 above employingPRX-002 (−) isomer, (330 mg, 1.55 mmol) and pivalic acid (317 mg, 3.11mmol), provided the product (PRX-P5-007) (236 mg, 40% yield) as a yellowliquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.32-7.27 (m, 4H), 7.22-7.17 (m, 1H), 6.87 (q,J=5.2 Hz, 1H), 4.35-4.31 (m, 1H), 3.61-3.54 (m, 1H), 3.25-3.16 (m, 1H),2.90 (d, J=8.0 Hz, 1H), 2.60 (s, 1H), 2.47-2.46 (d, J=3.2 Hz, 1H),1.78-1.60 (m, 3H), 1.55-1.44 (m, 4H), 1.26-1.24 (m, 2H), 1.20-1.18 (s,9H), 1.10-1.06 (m, 3H) [M+Na]⁺=410.2

Example 26. PRX-P5-008N-(1-(Z)-Octadec-9-enoyloxy)ethoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as (Z)-Octadec-9-enoic Acid1-[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyloxy]-ethyl Ester)

Using the general procedure described in Example 18 above employingPRX-002 (−) isomer, (0.6 g, 2.79 mmol) and oleic acid (1.58 g, 5.60mmol), provided the product (PRX-P5-008) (0.55 g, 35% yield) as a yellowliquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.33-7.27 (m, 4H), 7.22-7.18 (m, 1H), 6.87 (q,J=5.6 Hz, 1H), 5.36-5.33 (m, 2H), 4.35-4.32 (m, 1H), 3.59-3.55 (m, 1H),3.24-3.18 (m, 1H), 2.89-2.88 (d, J=3.6 Hz, 1H), 2.61 (s, 1H), 2.44-2.43(m, 1H), 2.32-2.27 (m, 2H), 2.01-1.98 (m, 4H), 1.76-1.68 (m, 2H),1.61-1.57 (m, 3H), 1.54-1.51 (m, 2H), 1.29-1.24 (m, 24H), 1.09 (s, J=6.8Hz, 3H), 0.90 (t, J=6.8 Hz, 3H)

[M+Na]⁺=590.3

Example 27. PRX-P5-009N-(1-Tetradecanoyloxyethoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as Tetradecanoic acid1-[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyloxy]-ethyl Ester)

Using the general procedure described in Example 18 above employingPRX-002 (−) isomer, (330 mg, 1.55 mmol) and tetradecanoic acid (690 mg,3.06 mmol), provided the product (PRX-P5-009) (310 mg, 40% yield) as ayellow liquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.32-7.27 (m, 4H), 7.22-7.18 (m, 1H), 6.87 (q,J=5.2 Hz, 1H), 4.35-4.32 (m, 1H), 3.59-3.56 (m, 1H), 3.24-3.18 (m, 1H),2.89 (d, J=6 Hz, 1H), 2.61 (s, 1H), 2.44 (d, J=4 Hz, 1H), 2.32-2.25 (m,2H), 1.75-1.60 (m, 2H), 1.55-1.47 (m, 4H), 1.34-1.25 (m, 25H), 1.10 (t,J=7.2 Hz, 3H), 0.90 (t, J=6.8 Hz, 3H)

[M+Na]⁺=536.3

Example 28. PRX-P5-010N-(1-Hexradecanoyloxyethoxycarbonyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as Hexadecanoic Acid1-[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyloxy]-ethyl Ester)

Using the general procedure described in Example 18 above employingPRX-002 (−) isomer, (0.6 g, 2.79 mmol) and hexadecanoic acid (1.43 g,5.60 mmol), provided the product (PRX-P5-010) (0.6 g, 40% yield) as ayellow liquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.33-7.27 (m, 4H), 7.22-7.18 (m, 1H), 6.87 (q,J=5.2 Hz, 1H), 4.35-4.32 (m, 1H), 3.59-3.56 (m, 1H), 3.28-3.16 (m, 1H),2.89-2.87 (d, J=6 Hz, 1H), 2.61 (s, 1H), 2.44 (d, J=4.4 Hz, 1H),2.34-2.28 (m, 2H), 1.75-1.68 (m, 2H), 1.64-1.58 (m, 1H), 1.54-1.47 (m,4H), 1.34-1.26 (m, 28H), 1.09 (t, J=6.8 Hz, 3H), 0.90 (t, J=6.8 Hz, 3H)

[M+Na]⁺=564.3

Example 29. PRX-P5-011N-(1-Octadecanoyloxyethoxycarbonyl)-(+)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as Octadecanoic Acid 1-[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyloxy]-ethyl Ester)

Using the general procedure described in Example 18 above employingPRX-002 (+) isomer, (5 g, 23.22 mmol) and octadecanoic acid (13.27 g,46.68 mmol), provided the product (PRX-P5-011) (5.82 g, 44% yield) as apale yellow liquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.33-7.28 (m, 4H), 7.22-7.18 (m, 1H), 6.87 (q,J=5.6 Hz, 1H), 4.35 (d, J=5.6 Hz, 1H), 3.59 (t, J=6.8 Hz, 1H), 3.24-3.18(m, 1H), 2.89 (d, J=6.4 Hz, 1H), 2.61 (s, 1H), 2.44-2.43 (m, 1H),2.32-2.27 (m, 2H), 1.75-1.68 (m, 2H), 1.64-1.58 (m, 2H), 1.54-1.51 (m,1H), 1.50-1.47 (m, 3H), 1.32-1.25 (m, 31H), 1.09 (t, J=6.8 Hz, 3H), 0.90(t, J=6.8 Hz, 3H) [M+Na]⁺=592.30

Example 30. General Synthetic Procedure for PRX-P6-001 to PRX-P6-007

Step 1: To a solution of Boc-A1 (1.2 eq) in DMF (5 volumes) was addedHATU (1.5 eq), Et₃N (2 eq) and the reaction was stirred for 20 min.Then, a solution of PRX-002 (1 eq) in DMF (5 volumes) was introduceddropwise and the reaction mixture was stirred at ambient temperature for12 hours. After the completion of reaction (TLC eluent: 40% EtOAc inpetroleum ether), the reaction was quenched with ice cold water (20volumes) and extracted with ethyl acetate (2×10 volumes). The combinedorganic layer was washed with 3% citric acid solution (2×10 volumes),saturated NaHCO₃ solution (2×10 volumes) and brine solution (20volumes). The combined organic layer was dried over anhydrous sodiumsulfate, concentrated under reduced pressure. The crude product thusobtained was purified using flash column chromatography to yield theintermediate I-10.

Step 2: To a solution of intermediate I-10 (1 eq) in DCM (5 volumes) wasadded TFA (15 volumes) dropwise at 0-5° C. and the mixture was stirredfor 30 min at ambient temperature. After the completion of reaction (TLCeluent: 80% EtOAc in petroleum ether), the reaction mixture wasconcentrated under reduced pressure to remove TFA. The residue thusobtained was washed with hexane to give thick and brownish liquid, whichwas dissolved in ethyl acetate (2×20 volumes) and then washed withsaturated aq. NaHCO₃ solution (20 volumes) and brine (20 volumes). Thecombined EtOAc organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give intermediate I-11 as asticky brownish semi solid mass.

Step 3: To a solution of intermediate Boc-A₂ (1.2 eq) in DMF (5 volumes)was added HATU (1.5 eq), Et₃N (2 eq) and the mixture was stirred for 20min. Then, a solution of I-11 (1 eq) in DMF (5 volumes) was addeddropwise and the reaction was kept under stirring for 12 hours atambient temperature. After the completion of reaction (TLC eluent: 40%EtOAc in petroleum ether), the reaction was quenched with ice cold water(20 volumes), and extracted with ethyl acetate (2×10 volumes). Thecombined organic layer was washed with 3% aq. citric acid solution (2×10volumes), saturated NaHCO₃ solution (2×10 volumes) and brine solution(20 volumes), over anhydrous sodium sulfate and concentrated underreduced pressure. The crude product thus obtained was purified usingflash column chromatography to yield intermediate I-12.

Step 4: To a solution of intermediate I-12 (1 eq) in DCM (5 volumes) wasadded TFA (15 volumes) dropwise at 0-5° C. and the mixture was stirredfor 30 min at ambient temperature. After the completion of reaction (TLCeluent: 80% EtOAc in petroleum ether), the reaction mixture wasconcentrated under reduced pressure for the removal of TFA and then theresidue was washed with hexane to remove impurities. The thick liquidbrownish residue thus obtained was dissolved in ethyl acetate (2×20volumes), neutralized using saturated aq. NaHCO₃ solution (20 volumes)and washed with brine solution (20 volumes). The combined organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure to give dipeptide linked prodrugs, including PRX-P6-001 toPRX-P6-007 as a sticky gummy brownish mass. For the present example, Rdenotes the atoms for the noted compounds PRX-P6-001 to PRX-P6-007.

Example 31. PRX-P6-001N-(Glycyl-glycyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine (AlsoKnown as2-(2-Aminoacetamido)-N-ethyl-N-(3-phenylbicyclo[2.2.1]heptan-2-yl)acetamide)

Using the general procedure described in Example 30 above employingPRX-002 (−) isomer, (500 mg) and Boc-glycine (820 mg), provided theproduct (PRX-P6-001) (450 mg, 60% yield) as a off white solid.

¹H-NMR (CDCl₃, 400 MHz) δ 8.03 (s, 1H), 7.30-7.21 (m, 5H), 4.71 (s, 1H),4.23-3.97 (m, 3H), 3.49-3.19 (m, 2H), 2.90 (s, 1H), 2.58-2.41 (m, 2H),1.81 (m, 4H), 1.54-1.50 (m, 3H), 1.26 (s, J=5.6 Hz, 3H)

[M+H]⁺=330.50

Example 32. PRX-P6-002N-(Valyl-D-valyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine (AlsoKnown as(S)-2-Amino-N—{(R)-1-[ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyl]-2-methyl-propyl}-3-methyl-butyramide)

Using the general procedure described in Example 30 above employingPRX-002 (−) isomer, (500 mg), Boc-D-Valine (269 mg) and Boc-L-Valine(353 mg), provided the product (PRX-P6-002) (337 mg, 35% yield) as anoff white solid.

¹H NMR (CDCl₃, 400 MHz) δ 7.54-7.48 (m, 2H), 7.32-7.27 (m, 5H),7.25-7.18 (m, 1H), 4.85-4.77 (m, 3H), 4.31-4.28 (t, J=4.4 Hz, 1H),4.06-4.01 (q, J=6.8 Hz, 1H), 3.70-3.64 (m, 1H), 3.43-3.37 (m, 1H),3.13-3.09 (m, 1H), 2.72 (s, 1H), 1.95-1.92 (J=10.8 Hz, 1H), 1.60-1.47(m, 2H), 1.25-1.22 (dd, J=1.2 Hz & 10.4 Hz, 2H), 1.19-1.12 (m, 2H), 1.01(s, 3H), 0.82 (d, 6H), 0.72 (d, J=6.8 Hz, 6H) [M+H]⁺=414.2

Example 33. PRX-P6-003N-(Glycyl-Alanyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine (AlsoKnown as(S)-2-(2-Amino-acetylamino)-N-ethyl-N-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-propionamide)

Using the general procedure described in Example 30 above employingPRX-002 (−) isomer, (500 mg), Boc-L-alanine (269 mg) and Boc-glycine(292 mg), provided the product (PRX-P6-003) (344 mg, 44% yield) as apale yellow liquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.92 (t, 2H), 7.70 (d, J=5.8 Hz, 1H),7.34-7.27 (m, 3H), 7.24-7.18 (m, 2H), 4.97-4.89 (m, 1H), 4.48 (s, 1H),4.30 (s, 1H), 4.12-4.11 (m, 1H), 4.04-3.99 (m, 1H), 3.80-3.65 (m, 1H),3.59-3.57 (m, 1H), 3.43-3.39 (m, 1H), 3.36-3.35 (m, 2H), 3.30-3.21 (m,1H), 3.03-3.01 (d, J=6 Hz, 1H), 2.73 (s, 1H), 2.57-2.42 (m, 2H), 1.30(d, J=5.8 Hz, 3H), 1.03 (s, J=5.6 Hz, 3H)

[M+H]⁺ 344.47, found 344.1

Example 34. PRX-P6-004N-(Valyl-valyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine (AlsoKnown as(S)-2-Amino-N—{(S)-1-[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyl]-2-methyl-propyl}-3-methyl-butyramide)

Using the general procedure described in Example 30 above employing,PRX-002 (−) isomer, (500 mg) and Boc-L-Valine (987 mg), provided theproduct (PRX-P6-004) (386 mg, 40% yield) as a off white solid.

¹H NMR (CDCl₃, 400 MHz) δ 7.90-7.83 (m, 1H), 7.34-7.27 (m, 4H),7.22-7.19 (m, 1H), 4.85-4.77 (m, 3H), 4.31-4.28 (t, J=4.4 Hz, 1H), 4.06(q, J=6.8 Hz, 1H), 3.70-3.64 (m, 1H), 3.43-3.37 (m, 1H), 3.13-3.09 (m,1H), 2.72 (s, 1H), 1.95 (d, J=10.8 Hz, 1H), 1.60-1.47 (m, 2H), 1.25 (dd,J=1.2 Hz & 10.4 Hz, 2H), 1.19-1.12 (m, 2H), 1.01 (s, 3H), 0.82 (d, 6H),0.72 (d, J=6.8 Hz, 6H)

[M+H]⁺=414.2

Example 35. PRX-P6-005N-(Phenylalanyl-phenylalanyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as(S)-2-Amino-N—{(S)-1-[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyl]-2-phenyl-ethyl}-3-phenyl-propionamide)

Using the general procedure described in Example 30 above employingPRX-002 (−) isomer, (0.7 g) and Boc-L-Phenyl alanine (1.643 g), providedthe product (PRX-P6-005) (0.594 g, 36% yield) as a yellow liquid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.90-7.83 (m, 3H), 7.33-7.27 (m, 4H),7.24-7.10 (m, 11H), 5.17-5.00 (m, 1H), 4.76-4.37 (m, 1H), 3.74-3.68 (m,1H), 3.61-3.55 (m, 1H), 3.20-3.10 (m, 2H), 3.08-2.98 (m, 2H), 2.90-2.78(m, 2H), 2.74-2.50 (m, 2H), 2.45-2.30 (m, 1H), 1.56-1.42 (m, 2H),1.32-1.18-1.16 (m, 2H), 1.15 (s, J=5.7 Hz, 3H), 0.85-0.77 (m, 1H)

[M+H]⁺=510.3

Example 36. PRX-P6-006N-(Alanyl-glycyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine (AlsoKnown as (S)-2-Amino-N—{[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyl]-methyl}-propionamide)

Using the general procedure described in Example 30 above employingPRX-002 (−) isomer, (500 mg), Boc-L-Alanine (283 mg) and Boc-glycine(488 mg), provided the product (PRX-P6-006) (305 mg, 38% yield) as ayellow liquid.

¹H NMR (CDCl₃, 400 MHz) δ 8.07-8.05 (m, 1H), 7.33-7.29 (m, 3H),7.27-7.21 (m, 3H), 4.71 (s, 1H), 4.20-3.91 (m, 4H), 3.66 (s, 1H), 3.35(s, 1H), 3.20 (d, J=7.2 Hz, 1H), 2.91 (s, 1H), 2.81-2.75 (m, 1H),2.57-2.42 (m, 1H), 2.22-2.01 (m, 2H), 1.82-1.64 (m, 2H), 1.39-1.30 (m,1H), 1.28-1.10 (m, 6H)

[M+H]⁺=344.2

Example 37. PRX-P6-011N-(Valyl-valyl)-(+)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine (alsoknown as(S)-2-Amino-N—{(S)-1-[N-ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyl]-2-methyl-propyl}-3-methyl-butyramide)

Using the general procedure described in Example 30 above employingPRX-002 (+) isomer, (4 g) and Boc-L-Valine (7.9 g), provided theproduct,

(PRX-P6-011) (3 g, 39% yield) as a colorless semisolid.

¹H-NMR (CDCl₃, 400 MHz) δ 7.90-7.83 (m, 1H), 7.34-7.27 (m, 4H),7.22-7.19 (m, 1H), 4.85-4.77 (m, 3H), 4.31-4.28 (t, J=4.4 Hz, 1H), 4.06(q, J=6.8 Hz, 1H), 3.70-3.64 (m, 1H), 3.43-3.37 (m, 1H), 3.13-3.09 (m,1H), 2.72 (s, 1H), 1.95 (d, J=10.8 Hz, 1H), 1.60-1.47 (m, 2H), 1.25 (dd,J=1.2 Hz & 10.4 Hz, 2H), 1.19-1.12 (m, 2H), 1.01 (s, 3H), 0.82 (d, 6H),0.72 (d, J=6.8 Hz, 6H)

[M+H]⁺=414.2

Example 38. PRX-P6-007N—(N6-Lysyl-lysyl)-(−)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine(Also Known as (S)-2,6-Diamino-hexanoic acid{(S)-5-amino-5-[ethyl-(3-phenyl-bicyclo[2.2.1]hept-2-yl)-carbamoyl]-pentyl}-amide)

Step 1: To a solution of Boc-Lys(Z)—OH (1.27 g) in DMF (7 mL) was addedHATU (1.6 g), Et₃N (0.65 mL). After 20 minute stirring, PRX-002 (−)isomer (0.6 g) in DMF (3 mL) was added dropwise and the reaction mixturewas stirred for 12 hours at ambient temperature. After the completion ofreaction (TLC eluent: 40% EtOAc in petroleum ether), the reaction wasquenched with ice cold water (150 mL) and extracted with ethyl acetate(2×70 mL). The combined organic layer was washed with 3% citric acidsolution (2×50 mL), saturated NaHCO₃ solution (2×50 mL) and brine (50mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure. The crude product thus obtained was purified using flashcolumn chromatography to afford intermediate I-13.

Step 2: To a solution of I-13 (1.3 g) in methanol (50 mL) was added 10%Pd/C (1.3 g, 100% w/w) and the mixture was kept under H₂ (60 psi) for 8h in Parr-shaker. After the completion of reaction (TLC eluent: 10% MeOHin DCM), the reaction mixture was filtered through Celite bed and thefiltrate was concentrated under reduced pressure to yield intermediateI-14 as a thick pale yellow liquid.

Step 3: To a solution of Boc-Lys(Z)—OH (0.87 g) in DMF (7 mL) was addedHATU (1.09 g), Et₃N (0.6 mL). After stirring for 20 minutes, a solutionof I-14 (0.85 g) in DMF (3 mL) was added dropwise and the reactionmixture was stirred for 12 hours at ambient temperature. After thecompletion of reaction (TLC eluent: 40% EtOAc in petroleum ether), thereaction was quenched with ice cold water (150 mL) and extracted withethyl acetate (2×70 mL). The combined organic layer was washed with 3%citric acid solution (2×50 mL), saturated NaHCO₃ solution (2×50 mL) andbrine solution (50 mL). The combined organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude product thus obtained was purified using flash columnchromatography to give intermediate I-15.

Step 4: To a solution of I-15 (1.5 g) in DCM (15 mL) was added TFA (20mL) dropwise at 0-5° C. and the reaction mixture was stirred for 30 minat ambient temperature. After the completion of reaction (TLC eluent:10% MeOH in DCM), the reaction mixture was concentrated under reducedpressure for the removal of TFA. The residue thus obtained was washedwith hexane for removal of impurities and yielding thick liquid brownishmass, which was further dissolved in ethyl acetate (50 mL), neutralizedusing saturated aq. NaHCO₃ (30 mL) solution and washed with brinesolution (30 mL). The ethyl acetate layer was dried over anhydroussodium sulfate and concentrated under reduced pressure to affordintermediate I-16 as a sticky gummy brownish mass.

Step 5: To a solution of I-16 (0.78 g) in methanol (50 mL) was added 10%Pd/C (0.78 g, 100% w/w) and the mixture was kept under H₂ pressure of 60psi. for 8 hours in Parr-shaker. After the completion of reaction (TLCeluent: 10% MeOH in DCM), the mixture was filtered through Celite andthe filtrate was concentrated under reduced pressure. The crude productobtained was purified by using preparative HPLC to yield the product(PRX-P6-007) (0.4 g, 30% yield) as a thick pale yellow liquid.

¹H-NMR (DMSO-ds, 400 MHz) δ 8.49 (s, 1H) 7.78-7.65 (m, 1H), 7.35-7.17(m, 5H), 4.38-4.32 (m, 1H), 3.45-3.25 (m, 3H), 3.20-3.12 (m, 6H),2.52-2.45 (m, 3H), 2.35-2.31 (m, 4H), 1.87-1.20 (m, 18H), 1.01 (s, 3H)

[M+H]⁺=472.30

Example 39 Pharmacokinetic (PK) Profiles of Conjugates ofN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine

We describe here PK results of prodrugs of PRX-002 (−) or (+) isomers.All doses of prodrugs were administered such that they were equivalentto 5 mg/kg of PRX-002 (−) or (+) for oral studies and 2 mg/kg PRX-002(−) or (+) for intravenous studies in male Sprague-Dawley (MSD) rats.Higher doses of up to 10 or 15 mg/kg [again equivalent to PRX-002 (−)]were used in some studies (as specified)]. Formulation preparation, doseadministration and time of sample collection was as follows.

Oral Formulation Preparation:

Test item was weighed [5 mg equivalent dose of PRX-002 for prodrugs] andtransferred to a graduated tube. Then 10 μL of Tween 80 was added andvortexed mixed until the test item was completely mixed. Small volume of0.5% (w/v) carboxymethylcellulose in water solution was then addeddropwise with continuous vortex mixing until a uniform suspension wasobtained. The final volume was then made up to 10 mL with 0.5% (w/v)carboxymethylcellulose in water with final strength of 0.5 mg/mL. Theobtained formulation was found to be uniform suspension. Thisformulation was freshly prepared before the administration to animals.

Oral Dose Administration:

Adult male Sprague Dawley Rats aged 8-10 weeks were used for the study.Fasted animals were administered test item by oral route with a dose of5 mg/kg body weight at dose volume of 10 mL/kg body weight. Under mildisoflurane anesthesia, blood specimens were collected by retro-orbitalpuncture method using capillary tubes into pre-labeled tubes containinganticoagulant (K₂EDTA-2 mg/mL blood) during the next 24 hours of postdose as mentioned in below table. For blood sampling at multiple timepoints, right and left eyes were used alternatively for bloodcollection. Collected blood specimens were centrifuged at 4000 rpm, 4°C. for 10 minutes and plasma were separated and stored at −80° C. untilanalysis.

Blood was collected as outlined in Table 39.1 (oral).

TABLE 39.1 Ani- Group mal Blood collection time points (h) no. ID 0.080.25 0.50 1.00 2.00 4.00 6.00 24.00 G-X R00X X X X X X X X X R00X X X XX X X X X R00X X X X X X X X X

IV Formulation Preparation:

Test item was weighed [(to be equivalent to 2 mg/kg of PRX 002 dose] andtransferred to a graduated tube. Then 500 μL of PEG 400 (v/v) was addedand vortex mixed thoroughly until the test item was completelydissolved. Then 1500 μL of Hydroxypropyl-3-cyclodextrin (HPβCD, 50% w/v)was added and vortex mixed thoroughly. The final volume was then made upto 5000 μL with sterile water for injection (SWFI, v/v) with finalformulation strength of 0.4 mg/mL. The obtained formulation was found tobe clear solution. This formulation was freshly prepared before theadministration to animals.

IV Dose Administration:

Adult male Sprague Dawley Rats aged 8-10 weeks were used for the study.Animals were administered the test item by Intravenous bolus route witha dose of 2 mg/kg body weight at dose volume of 5.0 mL/kg body weight.Under mild isoflurane anesthesia, blood specimens were collected byretro-orbital puncture method using capillary tubes into pre-labeledtubes containing anticoagulant (K₂EDTA-2 mg/mL blood) during the next 24hours of post dose as mentioned in below table. For blood sampling atmultiple time points, right and left eyes were used alternatively forblood collection. Collected blood specimens were centrifuged at 4000rpm, 4° C. for 10 minutes and plasma were separated and stored at −80°C. until analysis.

Blood was collected as outlined in Table 39.2 (IV).

TABLE 39.2 Blood collection time points (h) Group no. Animal ID 0.080.25 0.50 1.00 2.00 4.00 6.00 24.00 G-x R00x X X X X X X X X R00X X X XX X X X X R00X X X X X X X X XHigher Dose Oral Formulation and Dose Administration for PRX-P4-003 [10mg/kg Dose Equivalent of PRX-002 (−)]

Formulation Preparation:

Test item PRX-P4-003 was weighed and transferred to a graduated tube.Then 12.42 μL of Tween 80 was added and vortexed mixed until the testitem was completely mixed. Small volume of 0.5% (w/v)Carboxymethylcellulose in water solution was then added dropwise withcontinuous vortex mixing until a uniform suspension was obtained. Thefinal volume was then made up to 12.42 mL with 0.5% (w/v)Carboxymethylcellulose in water with final strength of 1.0 mgA/mL. Theobtained formulation was found to be uniform suspension. Thisformulation was freshly prepared before the administration to animals.

Dose Administration:

Adult male Sprague Dawley Rats aged 8-10 weeks were used for the study.Fasted animals were administered with a PRX-P4-003 by oral route with adose of 10 mg/kg body weight at dose volume of 10 mL/kg body weight.Under mild isoflurane anesthesia, blood specimens were collected byretro-orbital puncture method using capillary tubes into pre-labeledtubes containing anticoagulant (K₂EDTA-2 mg/mL blood) during the next 24hours of post dose as mentioned in below table. For blood sampling atmultiple time points, right and left eyes were used alternatively forblood collection. Collected blood specimens were centrifuged at 4000rpm, 4° C. for 10 minutes and plasma were separated and stored at −80°C. until analysis.

Higher Dose IV Formulations and Administration for PRX-P4-003 [10 mg/kgDose Equivalent of PRX-002 (−)]

Formulation Preparation [PRX-P4-003 dose equivalent of 10 mg/kg PRX-002(−)]:

Test item PRX-P4-003 was weighed and transferred to a graduated tube.Then 600 μL of PEG 400 (v/v) was added and vortex mixed thoroughly untilthe test item was completely dissolved. Then 1.800 mL ofHydroxypropyl-β-cyclodextrin (HPβCD, 50% w/v) was added and vortex mixedthoroughly. The final volume was then made up to 3.600 mL with sterilewater for injection (SWFI, v/v) with final formulation strength of 5.16mgA/mL. The obtained formulation was found to be colloidal solution.This formulation was freshly prepared before the administration toanimals.

Dose Administration:

Adult male Sprague Dawley Rats aged 8-10 weeks were used for the study.Animals were administered with a PRX-P4-003 by Intravenous bolus routewith a dose of 10 mg/kg body weight at dose volume of 5 mL/kg bodyweight. Under mild isoflurane anesthesia, blood specimens were collectedby retro-orbital puncture method using capillary tubes into pre-labeledtubes containing anticoagulant (K₂EDTA-2 mg/mL blood) during the next 24hours of post dose as mentioned in below table. For blood sampling atmultiple time points, right and left eyes were used alternatively forblood collection. Collected blood specimens were centrifuged at 4000rpm, 4° C. for 10 minutes and plasma were separated and stored at −80°C. until analysis.

Higher Dose Oral Formulation and Dose Administration for PRX-P5-006 [15mg/kg Dose Equivalent of PRX-002 (−)]

Formulation Preparation:

Test item PRX-P5-006 was weighed and transferred to a graduated tube.Then 10 μL of Tween 80 was added and vortexed mixed until the test itemwas completely mixed. Small volume of 0.5% (w/v) Carboxymethylcellulosein water solution was then added dropwise with continuous vortex mixinguntil a uniform suspension was obtained. The final volume was then madeup to 10 mL with 0.5% (w/v) Carboxymethylcellulose in water with finalstrength of 3.97 mg/mL. The obtained formulation was found to be uniformsuspension. This formulation was freshly prepared before theadministration to animals.

Dose Administration:

Adult male Sprague Dawley Rats aged 8-10 weeks were used for the study.Fasted animals were administered with a PRX-P5-006 by oral route with adose of 15 mg/kg body weight at dose volume of 10 mL/kg body weight.Under mild isoflurane anesthesia, blood specimens were collected byretro-orbital puncture method using capillary tubes into pre-labeledtubes containing anticoagulant (K₂EDTA-2 mg/mL blood) during the next 24hours of post dose as mentioned in below table. For blood sampling atmultiple time points, right and left eyes were used alternatively forblood collection. Collected blood specimens were centrifuged at 4000rpm, 4° C. for 10 minutes and plasma were separated and stored at −80°C. until analysis.

Higher Dose IV Formulation and Dose Administration for PRX-P5-006 [15mg/kg Dose Equivalent of PRX-002 (−)]

Formulation Preparation:

Test item PRX-P5-006 was weighed and transferred to a graduated tube.Then 500 μL of DMSO (v/v) was added vortex mixed thoroughly until thetest item was completely dissolved. Then 4000 μL ofHydroxypropyl-β-cyclodextrin (HPβCD, 50% w/v) was added and vortex mixedthoroughly. Then 2500 μL of PEG 400 (v/v) was added and vortex mixedthoroughly. The final volume was then made up to 10000 μL with sterilewater for injection (SWFI, v/v) with final formulation strength of 3.97mg/mL. The obtained formulation was found to be clear solution. Thisformulation was freshly prepared before the administration to animals.

Dose Administration:

Adult male Sprague Dawley Rats aged 8-10 weeks were used for the study.Animals were administered with a PRX-P5-006 by Intravenous bolus routewith a dose of 15 mg/kg body weight at dose volume of 10 mL/kg bodyweight. Under mild isoflurane anesthesia, blood specimens were collectedby retro-orbital puncture method using capillary tubes into pre-labeledtubes containing anticoagulant (K₂EDTA-2 mg/mL blood) during the next 24hours of post dose as mentioned in below table. For blood sampling atmultiple time points, right and left eyes were used alternatively forblood collection. Collected blood specimens were centrifuged at 4000rpm, 4° C. for 10 minutes and plasma were separated and stored at −80°C. until analysis.

Table 39.3 depicts a set of comparative data of single dose oral andintravenous PIK Study of PRX-P4-003. Additional data in this regard ispresented in FIG. 1.

TABLE 39.3 Single Dose Oral and Intravenous PK Study of PRX-P4-003 inMale Sprague Dawley Rats Oral Intravenous PK Parameters Mean Plasma PKParameters of PRX-P4-003 Dose (mg/kg) 5.00 2.00 C_(max) (ng/mL) 0.0 ±0.0 171.963 ± 62.6030  T_(max) (hr) 0.0 ± 0.0 0.080 ± 0.0000 AUC_(last)(hr*ng/mL) 0.0 ± 0.0 132.573 ± 32.5110  AUC_(inf) (hr*ng/mL) 0.0 ± 0.0215.708 ± 83.3890  AUC_(% extrap) (%) 0.0 ± 0.0 32.475 ± 83.3890 Vss(L/kg) 0.0 ± 0.0 41.984 ± 19.8767 CL (mL/min/kg) 0.0 ± 0.0 171.947 ±69.3217  T_(1/2) (hr) 0.0 ± 0.0 3.348 ± 2.1780 MRT_(last) (hr) 0.0 ± 0.01.836 ± 0.7130

FIG. 2 is a graph depicting oral and IV pharmacokinetics for PRX-P4-003in male Sprague Dawley rats. The graph depicts the results for theresulting plasma concentration of PRX-002(−) isomer via oral or IVadministration. As can be seen, while oral administration results in adesired plasma concentration for the active/parent drug (here,PRX-002(−) isomer), IV administration results in minimal amounts of anyof the PRX-P4-003 being converted from the pro-drug form to the activeform. The results are outlined above in Table 39.4 and 39.5.

TABLE 39.4 COMPARATIVE DATA: SINGLE DOSE ORAL AND INTRAVENOUS PK STUDYOF PRX-P4-003 IN MALE SPRAGUE DAWLEY RATS. Mean Plasma PK Parameters ofPRX-002 (−) Isomer A B C D Dose (mg/kg) 5.00 (oral) 10.00 (oral) 2.00(IV) 10.00 (IV) C_(max) (ng/mL) 156.7030 ± 85.32600  425.0400 ±40.46000  30.807 ± 10.0830 NC T_(max) (hr) 0.8330 ± 0.28900 1.3330 ±0.57700 0.080 ± 0.0000 NC AUC_(last) (hr*ng/mL) 296.8610 ± 51.2400 1092.8470 ± 169.08500  14.254 ± 3.8510  NC AUC_(inf) (hr*ng/mL) 308.8410± 58.24000  1158.6130 ± 137.93700  22.098 ± 7.0600  NC AUC_(% extrap)(%)3.6430 ± 2.29800 5.9310 ± 3.20800 34.822 ± 6.9490  NC Vss (L/kg) —86.814 ± 23.2576 NC CL (mL/min/kg) — 1606.391 ± 464.8270  NC T_(1/2)(hr) 1.8080 ± 0.30700 1.9220 ± 0.09300 0.682 ± 0.2440 NC MRT_(last) (hr)1.2770 ± 0.25600 1.2890 ± 0.29000 0.340 ± 0.0190 NC A: Oral PK (5 mg/kg)B: Oral PK (10 mg/kg) C: Intravenous PK (2 mg/kg) D: Intravenous PK (10mg/kg) *NC: Not Calculated. PRX-002 (−) Isomer IV 10 mg/kg PK dataanalysis was not carried out because limited exposure in plasmaconcentration profile

TABLE 39.5 Concentration time profile of PRX-002 (−) after oral and IVdose of PRX-P4-003 Single Dose Oral and Intravenous PharmacokineticsStudy of PRX-P4-003 In Male Sprague Dawley Rats Oral PK Intravenous PKPlasma concentration of PRX-002 (−) Isomer (ng/mL) Time (h) Mean SD Time(h) Mean ± SD 0.00 0.00 ± 0.00 0.00 — ± — 0.08 0.00 ± 0.00 0.08 30.81 ±10.08 0.25 35.89 ± 18.38 0.25 15.63 ± 3.90 0.50 97.56 ± 29.02 0.50 9.14± 3.39 1.00 149.74 ± 89.23 1.00 7.82 ± 0.92 2.00 56.12 ± 21.49 2.00 0.00± 0.00 4.00 25.08 ± 11.71 4.00 0.00 ± 0.00 6.00 6.10 ± 3.79 6.00 0.00 ±0.00 24.00 0.00 ± 0.00 24.00 0.00 ± 0.00

FIG. 3 depicts the results of the comparative data regarding IV PKstudies of PRX-P4-003 (2 and 10 mg/kg b.w.) PRX-002(−) isomer (2 mg/kgb.w.). As can be observed very limited amount of parent PRX-002 (−) isgenerated when the prodrug PRX-P4-003 is administered IV even at higherdose of 10 mg/kg. Additional data is summarized in Tables 39.6-39.7.

TABLE 39.6 Comparative Data: Intravenous PK Study of PRX-P4-003 (2 and10 mg/kg b.w.) and PRX-002 (−) Isomer (2 mg/kg b.w.) in Male SpragueDawley Rats IV PK Study of PRX-P4-003 IV PK Study of PRX-P4-003 IV PKStudy of PRX-002 (2 mg/kg b.w.) (10 mg/kg b.w.) (−) Isomer (2 mg/kgb.w.) Plasma concentration of Plasma concentration of Plasmaconcentration of Plasma concentration of Plasma concentration ofPRX-P4-003 PRX-002 (−) Isomer PRX-P4-003 PRX-002 (−) Isomer PRX-002 (−)Isomer Time (h) Mean SD Mean SD Mean ± SD Mean ± SD Mean ± SD 0.08171.96 ± 62.60 30.81 ± 10.08 199.64 ± 74.37 27.06 ± 6.80 142.01 ± 1.210.25 47.94 ± 20.26 15.63 ± 3.90 27.98 ± 10.03 6.59 ± 0.69 112.59 ± 28.480.50 26.73 ± 12.51 9.14 ± 3.39 8.96 ± 7.80 2.02 ± 1.79 81.21 ± 6.58 1.0020.03 ± 4.68 7.82 ± 0.92 0.00 ± 0.00 0.00 ± 0.00 58.82 ± 14.08 2.0018.29 ± 5.46 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 53.05 ± 8.64 4.00 14.23± 3.98 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 16.55 ± 6.41 6.00 10.72 ±11.52 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 24.00 0.00 ± 0.000.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00

TABLE 39.7 Comparative Data: Intravenous PK Study of PRX-P4-003 (2 and10 mg/kg b.w.) and PRX-002 (−) Isomer (2 mg/kg b.w.) in Male SpragueDawley Rats IV PK Study of IV PK Study of PRX-P4-003 IV PK Study ofPRX-P4-003 PRX-002 (−) Isomer (2 mg/kg b.w.) (10 mg/kg b.w.) (2 mg/kgb.w.) Mean Plasma PK Mean PK Parameters Mean PK Parameters Mean PKParameters Mean PK Parameters Mean PK Parameters Parameters ofPRX-P4-003 of PRX-002 (−) Isomer of PRX-P4-003 of PRX-002 (−) Isomer ofPRX-002 (−) Isomer Dose (mg/kg b.w.) 2 2 10 10 2 C_(max) (ng/mL) 171.963± 62.6030  30.807 ± 10.0830 NC NC 142.973 ± 1.7520  T_(max) (hr) 0.080 ±0.0000 0.080 ± 0.0000 NC NC  0.137 ± 0.0980 AUC_(last) (hr*ng/mL)132.573 ± 32.5110  14.254 ± 3.8510  NC NC 218.525 ± 23.9320 AUC_(inf)(hr*ng/mL) 215.708 ± 83.3890  22.098 ± 7.0600  NC NC 256.001 ± 44.2920AUC_(% extrap)(%) 32.475 ± 83.3890 34.822 ± 6.9490  NC NC 14.056 ±5.0710 Vss (L/kg) 41.984 ± 19.8767 86.814 ± 23.2576 NC NC 15.726 ±0.3391 CL (mL/min/kg) 171.947 ± 69.3217  1606.391 ± 464.8270  NC NC132.632 ± 21.0303 T_(1/2) (hr) 3.348 ± 2.1780 0.682 ± 0.2440 NC NC 1.512 ± 0.2230 MRT_(last) (hr) 1.836 ± 0.7130 0.340 ± 0.0190 NC NC 1.328 ± 0.1180 *NC: Not Calculated. PRX-P4-003 IV 10 mg/kg PK dataanalysis was not carried out because limited exposure in plasmaconcentration profile

FIG. 4 is a graph comparing the oral PK study of PRX-P4-003 toPRX-002(−) isomer, in terms of the amount of resulting PRX-P4-003 orPRX-P4-002(−) isomer present in the plasma. As can be seen from theresults, almost none of the prodrug form of the drug (PRX-P4-003) ispresent in the plasma when administered orally. However, a desiredamount of the active compound (PRX-002 (−) Isomer) does form in theplasma. Additional data is presented in Table 39.8-39.9

TABLE 39.8 ORAL PK STUDY OF PRX-P4-003 (5 AND 10 MG/KG) AND PRX-002(−)(5 MG/KG)IN MALE SPRAGUE DAWLEYRATS. MEAN PK PARAMETERS OF PRX-P4-003AND PRX-002 (−) ISOMER Oral PK Study of Oral PK Study of Oral PK Studyof PRX-P4-003 PRX-P4-003 PRX-002 (−) (5 mg/kg) (10 mg/kg) Isomer (5mg/kg) A B C D E Dose (mg/kg) 5.0 5.0 10.0 10.00 5.0 C_(max) (ng/mL) 0.0156.7030 ± 85.32600  0.0 425.0400 ± 40.46000  176.260 ± 47.4850 T_(max)(hr) 0.0 0.8330 ± 0.28900 0.0 1.3330 ± 0.57700  0.833 ± 0.2890AUC_(last) (hr*ng/mL) 0.0 296.8610 ± 51.2400  0.0 1092.8470 ± 169.08500 370.968 ± 99.4740 AUC_(inf)(hr*ng/mL) 0.0 308.8410 ± 58.24000  0.01158.6130 ± 137.93700   427.201 ± 122.1840 AUC_(% extrap)(%) 0.0 3.6430± 2.29800 0.0 5.9310 ± 3.20800 12.904 ± 1.8410 T_(1/2) (hr) 0.0 1.8080 ±0.30700 0.0 1.9220 ± 0.09300 1.864 ± 0.132 MRT_(last) (hr) 0.0 1.2770 ±0.25600 0.0 1.2890 ± 0.29000  1.474 ± 0.1040 A: Mean PK Parameters ofPRX-P4-003 B: Mean PK Parameters of PRX-002 (−) Isomer C: Mean PKParameters of PRX-P4-003 D: Mean PK Parameters of PRX-002 (−) Isomer E:Mean PK Parameters of PRX-002 (−) Isomer

TABLE 39.9 Comparative Data: Oral PK Study of PRX-P4-003 (5 and 10 mg/kgb.w.) and PRX-002 (−) Isomer (5 mg/kg b.w.) in Male Sprague Dawley RatsOral PK Study of PRX-P4-003 Oral PKStudy of PRX-P4-003 Oral PK Study ofPRX-002 (5 mg/kg b.w.) (10 mg/kg b.w.) (−) Isomer (5 mg/kg b.w.) Plasmaconcentration of Plasma concentration of Plasma concentration of Plasmaconcentration of Plasma concentration of PRX-P4-003 PRX-002 (−) IsomerPRX-P4-003 PRX-002 (−) Isomer PRX-002 (−) Isomer Time h) Mean SD Mean SDMean ± SD Mean ± SD Mean ± SD 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.000.00 ± 0.00 0.00 ± 0.00 0.08 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 2.52 ±4.37 0.00 ± 0.00 0.25 0.00 ± 0.00 35.89 ± 18.38 0.00 ± 0.00 118.79 ±44.28 50.20 ± 45.98 0.50 0.00 ± 0.00 97.56 ± 29.02 0.00 ± 0.00 285.18 ±84.86 159.35 ± 44.89 1.00 0.00 ± 0.00 149.74 ± 89.23 0.00 ± 0.00 414.87± 52.27 170.35 ± 43.09 2.00 0.00 ± 0.00 56.12 ± 21.49 0.00 ± 0.00 312.47± 78.99 101.07 ± 36.25 4.00 0.00 ± 0.00 25.08 ± 11.71 0.00 ± 0.00 74.52± 27.56 21.30 ± 10.18 6.00 0.00 ± 0.00 6.10 ± 3.79 0.00 ± 0.00 33.82 ±10.45 0.00 ± 0.00 24.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.000.00 ± 0.00

FIGS. 5 A and 5B shows comparative Data: Single Dose Oral andIntravenous PK Study of PRX-P5-006. Much higher level of intactPRX-P5-006 was observed when prodrug was administered IV. The data isshown in Table 39.10. Additional data is shown in Tables 39.11-39.12

TABLE 39.10 Single Dose Oral and Intravenous PK Study of PRX-P5-006 inMale Sprague Dawley Rats-amount of prodrug remaining in plasma OralIntravenous PK Parameters Mean Plasma PK Parameters of PRX-P5-006 Dose(mg/kg) 5.00 2.00 C_(max) (ng/mL) 61.457 ± 15.4180 9097.783 ± 1947.6780T_(max) (hr) 1.000 ± 0.0000  0.08 ± 0.0000 AUC_(last) (hr*ng/mL) 57.800± 10.1940 4267.485 ± 902.3590  AUC_(inf)(hr*ng/mL) 114.633 ± 23.3260 4563.103 ± 894.4610  AUC_(% extrap)(%) 47.896 ± 15.3010 6.602 ± 4.0330Vss (L/kg) — 1.875 ± 1.4500 CL (mL/min/kg) — 7.478 ± 1.3221 T_(1/2) (hr)2.907 ± 0.865  6.304 ± 3.7850 MRT_(last) (hr) 1.070 ± 0.0250 2.313 ±1.2350

TABLE 39.11 Single Dose Oral Pharmacokinetics Study of PRX-P5-006 inMale Sprague Dawley Rats (5 mg/kg b.w.) Animal No C_(max (ng/mL))T_(max (hr)) AUC_(last (hr*ng/mL)) AUC_(inf (hr*ng/mL)) AUC_(% extrap)MRT_(last (hr)) T_(1/2 (hr)) R001 43.87 1.00 46.56 122.60 62.02 1.103.50 R002 72.65 1.00 66.44 132.93 50.02 1.07 3.31 R003 67.85 1.00 60.4088.37 31.64 1.05 1.91 N 3 3 3 3 3 3 3 Mean 61.457 1.000 57.800 114.63347.896 1.070 2.907 SD 15.4180 0.0000 10.1940 23.3260 15.3010 0.02500.865

TABLE 39.12 Single Dose IV Pharmacokinetics Study of PRX-P5-006 in MaleSprague Dawley Rats (2 mg/kg b.w.) Ani- C₀ Vss CL mal No (ng/ml)C_(max (ng/mL)) T_(max (hr)) AUC_(last (hr*ng/mL)) AUC_(inf (hr*ng/mL))AUC_(% extrap) (L/kg) (mL/min/kg) MRT_(last (hr)) T_(1/2 (hr)) R00136229.68 11226.34 0.08 5304.3 5592.69 5.16 1.56 5.96 2.7 7.54 R00232467.12 8662.3 0.08 3838.58 3977.39 3.49 0.61 8.38 0.93 2.06 R00321202.31 7404.71 0.08 3659.58 4119.23 11.16 3.46 8.09 3.31 9.32 N 3 3 33 3 3 3 3 3 3 Mean 29966.370 9097.783 0.08 4267.485 4563.103 6.602 1.8757.478 2.313 6.304 SD 7819.5760 1947.6780 0.0000 902.3590 894.4610 4.03301.4500 1.3221 1.2350 3.7850

FIG. 6A is a graph depicting a comparison of oral and IVpharmacokinetics of PRX-P5-006 in Male Sprague Dawley rats. FIG. 6Bshows an enlarged view of the IV pharmacokinetics for the amount ofresulting active in the plasma depicted in 6A. The graph depicts theamount of the active compound found in the plasma over time for thePRX-P5-006 compound. The data is shown in Table 39.13, below. Additionaldata is shown below in Tables 39.14-39.17.

TABLE 39.13 COMPARATIVE DATA: SINGLE DOSE ORAL AND INTRAVENOUS PK STUDYOF PRX-P5-006 Single Dose Oral and Intravenous PK Study of PRX-P5- 006in Male Sprague Dawley Rats Oral Intravenous PK Parameters Mean PlasmaPK Parameters of PRX-002 Dose (mg/kg) 5.00 2.00 C_(max) (ng/mL) 85.297 ±24.4150  7.980 ± 1.9800 T_(max) (hr) 1.000 ± 0.0000  0.08 ± 0.0000AUC_(last) (hr*ng/mL) 226.99 ± 92.8790  9.750 ± 1.6650AUC_(inf)(hr*ng/mL) 241.836 ± 104.0180 21.703 ± 2.1980 AUC_(% extrap)(%)5.645 ± 1.8560 54.877 ± 7.6450 Vss (L/kg) — 304.212 ± 49.9758 CL(mL/min/kg) — 1547.056 ± 165.4562 T_(1/2) (hr) 1.290 ± 0.137   2.248 ±0.2880 MRT_(last) (hr) 2.061 ± 0.1540  0.874 ± 0.0360

TABLE 39.14 Single Dose Oral Pharmacokinetics Study of PRX-P5-006 inMale Sprague Dawley Rats (5 mg/kg b.w.) Plasma concentration of PRX-002(ng/mL) Group No. Time (h) R001 R002 R003 Mean SD G-1 0.00 0.00 0.000.00 0.000 0.000 0.08 0.00 0.00 0.00 0.000 0.000 0.25 2.82 8.21 4.475.167 2.761 0.50 32.44 49.39 53.68 45.169 11.230 1.00 67.50 113.13 75.2685.296 24.414 2.00 55.44 100.65 36.19 64.096 33.089 4.00 16.59 31.8113.28 20.561 9.884 6.00 4.82 13.82 4.56 7.735 5.269 24.00 0.00 0.00 0.000.000 0.000 LLOQ—Lower Limit Of Quantification of PRX-002 inplasma-2.167 ng/mL

TABLE 39.15 Single Dose Oral Pharmacokinetics Study of PRX-P5-006 inMale Sprague Dawley Rats (5 mg/kg b.w.) Animal No C_(max (ng/mL))T_(max (hr)) AUC_(last (hr*ng/mL)) AUC_(inf (hr*ng/mL)) AUC_(% extrap)MRT_(last (hr)) T_(1/2 (hr)) R001 67.50 1.00 184.54 192.44 4.10 2.091.14 R002 113.13 1.00 333.51 361.35 7.70 2.20 1.40 R003 75.26 1.00162.92 171.72 5.13 1.90 1.34 N 3 3 3 3 3 3 3 Mean 85.297 1.000 226.99241.836 5.645 2.061 1.29 SD 24.4150 0.0000 92.8790 104.0180 1.85600.1540 0.137

TABLE 39.16 (PLASMA CONCENTRATION OF ACTIVE) Single Dose IntravenousPharmacokinetics Study of PRX-P5-006 in Male Sprague Dawley Rats (2mg/kg b.w.) Plasma concentration of PRX-002 (ng/mL) Group No. Time (h)R004 R005 R006 Mean SD G-2 0.08 9.53 5.75 8.66 7.981 1.979 0.25 7.024.32 4.92 5.419 1.415 0.50 6.49 4.99 3.66 5.047 1.412 1.00 5.60 4.933.47 4.666 1.092 2.00 3.82 3.20 4.00 3.673 0.417 4.00 0.00 0.00 0.000.000 0.000 6.00 0.00 0.00 0.00 0.000 0.000 24.00 0.00 0.00 0.00 0.0000.000 LLOQ—Lower Limit Of Quantification of PRX-002 in plasma- 2.167ng/mL

TABLE 39.17 (PLASMA CONCENTRATION OF ACTIVE) Single Dose IVPharmacokinetics Study of PRX-P5-006 in Male Sprague Dawley Rats (2mg/kg b.w.) Ani- C₀ Vss CL mal No (ng/ml) C_(max (ng/mL)) T_(max (hr))AUC_(last (hr*ng/mL)) AUC_(inf (hr*ng/mL)) AUC_(% extrap) (L/kg)(mL/min/kg) MRT_(last (hr)) T_(1/2 (hr)) R001 11.00 9.53 0.08 11.6522.61 48.47 246.74 1474.36 0.83 1.99 R002 6.58 5.75 0.08 9.06 19.2052.82 328.45 1736.41 0.90 2.20 R003 11.30 8.66 0.08 8.54 23.30 63.34337.45 1430.39 0.89 2.56 N 3 3 3 3 3 3 3 3 3 3 Mean 9.627 7.980 0.0809.750 21.703 54.877 304.212 1547.056 0.874 2.248 SD 2.6450 1.9800 0.00001.6650 2.1980 7.6450 49.9758 165.4562 0.0360 0.2880

FIGS. 7A and 7B show graph depicting the IV pharmacokinetics forPRX-P5-011 in male Sprague Dawley rats. Even though the only differencebetween PRX-P5-011 and PRX-P5-006 is that the former has positive isomerPRX-002 (+) while the latter has PRX-002 (−) the oral plasma profile isremarkably different. The active compound PRX-002 (+) was not detectedin plasma after oral administration. The results are summarized abovefrom table 39.18-39.21

TABLE 39.18 SINGLE DOSE ORAL PHARMACOKINETIC STUDY OF PRX-P5-011PLASMACONCENTRATIONS OF PRX- P5-011 IN MALE SPRAGUE DAWLEY RATS. Plasmaconcentration of PRX-P5-011 (ng/mL) Time (h) R010 R011 R012 Mean SD 0.000.00 0.00 0.00 0.000 0.000 0.08 0.00 0.00 0.00 0.000 0.000 0.25 0.000.00 0.00 0.000 0.000 0.50 0.00 0.00 0.00 0.000 0.000 1.00 0.00 0.000.00 0.000 0.000 2.00 0.00 0.00 0.00 0.000 0.000 4.00 0.00 0.00 0.000.000 0.000 6.00 0.00 0.00 0.00 0.000 0.000 24.00 0.00 0.00 0.00 0.0000.000 LLOQ—Lower Limit Of Quantification of PRX-P5-011 in plasma-3.373ng/mL

TABLE 39.19 SINGLE DOSE ORAL PHARMACOKINETIC STUDY OF PRX-P5-011 PLASMACONCENTRATIONS OF PRX-002 (+) ISOMER IN MALE SPRAGUE DAWLEY RATS. Plasmaconcentration of PRX-002 (+) Isomer (ng/mL) Time (h) R010 R011 R012 MeanSD 0.00 0.00 0.00 0.00 0.000 0.000 0.08 0.00 0.00 0.00 0.000 0.000 0.250.00 0.00 0.00 0.000 0.000 0.50 0.00 0.00 0.00 0.000 0.000 1.00 0.000.00 0.00 0.000 0.000 2.00 0.00 0.00 0.00 0.000 0.000 4.00 0.00 0.000.00 0.000 0.000 6.00 0.00 0.00 0.00 0.000 0.000 24.00 0.00 0.00 0.000.000 0.000 LLOQ—Lower Limit Of Quantification of PRX-002 (+) isomer inplasma-1.779 ng/mL

TABLE 39.20 Single Dose Intravenous Pharmacokinetics Study of PRX-P5-011in Male Sprague Dawley Rats (2 mg/kg b.w.) Plasma concentration ofPRX-P5-011 (ng/mL) Group No. Time (h) R013 R014 R015 Mean SD G-2 0.08114.77 37.09 179.14 110.332 71.132 0.25 56.47 17.98 101.04 58.497 41.5630.50 0.00 0.00 0.00 0.000 0.000 1.00 0.00 0.00 0.00 0.000 0.000 2.000.00 0.00 0.00 0.000 0.000 4.00 0.00 0.00 0.00 0.000 0.000 6.00 0.000.00 0.00 0.000 0.000 24.00 0.00 0.00 0.00 0.000 0.000 LLOQ—Lower LimitOf Quantification of PRX-P5-011 in plasma-3.373 ng/nιL

TABLE 39.21 SINGLE DOSE IV PHARMACOKINETIC STUDY OF PRX-P5-011. PLASMACONCENTRATIONS OF PRX-002 (+) ISOMER IN MALE SPRAGUE DAWLEY RATS. SingleDose Intravenous Pharmacokinetics Study of PRX-P5-011 In Male SpragueDawley Rats (2 mg/kg b.w.) Plasma concentration of PRX-002 (+) Isomer(ng/mL) Group No. Time (h) R013 R014 R015 Mean SD G-2 0.08 8.92 2.527.77 6.400 3.409 0.25 0.00 0.00 0.00 0.000 0.000 0.50 0.00 0.00 0.000.000 0.000 1.00 0.00 0.00 0.00 0.000 0.000 2.00 0.00 0.00 0.00 0.0000.000 4.00 0.00 0.00 0.00 0.000 0.000 6.00 0.00 0.00 0.00 0.000 0.00024.00 0.00 0.00 0.00 0.000 0.000 LLOQ—Lower Limit Of Quantification ofPRX-002 (+) Isomer in plasma-1.779 ng/mL

FIG. 8A is a graph depicting the IV pharmacokinetics of PRX-P6-011 inmale Sprague Dawley rats. FIG. 8B is a more closely visualized graph(from 8A) consisting of PRX-P6-011, PRX-002 (+) [compared to the levelof PRX-002 (−) after direct administration]. The results are summarizedin tables 39.22-39.25.

Tables 39.22-39.25 provide comparative oral pharmacokinetics studyresults for PRX-P6-011 and PRX-002(+), including mean plasma PKparameters of PRX-P6-011, PRX-P1-006, PRX-002(+).

TABLE 39.22 Oral PK Study of PRX-P6-011 Oral PK Study of PRX- PRX-P1-002 (+) Isomer PRX-P6-011 006(monopeptide) PRX-002(+) Isomer PRX-002(+)Isomer Dose (mg/kg) 5.00 5.00 5.00 5.00 C_(max) (ng/mL) 82.223 ± 30.8790655.283 ± 193.0510 94.637 ± 26.1330 106.727 ± 25.432  T_(max) (hr) 0.137± 0.0980 0.833 ± 0.2890 0.750 ± 0.4330 0.5 ± 0.0 AUC_(last) (hr*ng/mL)44.161 ± 17.0700 1664.557 ± 363.7590  277.359 ± 69.7760  127.924±74.239  AUC_(inf) (hr*ng/mL) 57.261 ± 21.2510 1914.634 ± 367.6390 336.298 ± 37.4560  151.444 ± 68.603  AUC_(% extrap)(%) 23.190 ± 3.6640 13.391 ± 2.6780  18.346 ± 13.2530 18.063 ±11.646  T_(1/2) (hr) 1.172 ±0.2110 2.120 ± 0.3850 2.433 ± 1.0880 0.992 ± 0.228 MRT_(last) (hr) 0.575± 0.0370 1.885 ± 0.2180 2.002 ± 0.2090 0.957 ± 0.269

TABLE 39.23 Single Dose Oral Pharmacokinetics Study of PRX-P6- 011 inMale Sprague Dawley Rats (5 mg/kg b.w.) Plasma concentrations of Plasmaconcentrations of Plasma concentrations of PRX-P6-011 (ng/mL) PRX-P1-006(ng/mL) PRX-002 (+) Isomer (ng/mL) Time (h) Mean SD Mean ± SD Mean ± SD0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.08 75.92 ± 32.13 191.07 ±79.19 48.07 ± 20.49 0.25 62.77 ± 26.46 437.17 ± 222.28 86.02 ± 31.170.50 20.78 ± 9.87 617.34 ± 209.88 80.97 ± 26.95 1.00 13.01 ± 6.06 645.99± 179.41 93.49 ± 25.37 2.00 7.87 ± 2.93 336.43 ± 153.72 62.66 ± 23.234.00 0.00 ± 0.00 122.45 ± 13.35 21.38 ± 3.32 6.00 0.00 ± 0.00 83.31 ±13.47 16.05 ± 2.98 24.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00

TABLE 39.24 Single Dose Oral PK Study of PRX-002 (+Isomer) at 5 mg/kgbody weight in Male Sprague Dawley Rats Animal ID C_(max (ng/mL))T_(max (hr)) AUC_(last (hr*ng/mL)) AUC_(inf (hr*ng/mL)) AUC_(% extrap)MRT_(last (hr)) T_(1/2 (hr)) R0175 134.89 0.5 213.62 229.43 6.89 1.261.07 R0176 85.44 0.5 87 124.51 30.13 0.86 1.17 R0177 99.85 0.5 83.16100.4 17.17 0.75 0.74 N 3 3 3 3 3 3 3 Mean 106.727 0.5 127.924 151.44418.063 0.957 0.992 SD 25.432 0 74.239 68.603 11.646 0.269 0.228

TABLE 39.25 Single Dose Oral PK Study of PRX-002 (+isomer) at 5 mg/kgbody weight in Male Sprague Dawley Rats Mean Plasma PK ParametersParameters PRX-002 (+isomer) Dose (mg/kg b.w.) 5.00 C_(max) (ng/mL)106.727 ± 25.432  T_(max)(hr) 0.5 ± 0.0 AUC_(last) (hr*ng/mL) 127.924 ±74.239  AUC_(inf)(hr*ng/mL) 151.444 ± 68.603  AUC_(% extrap)(%) 18.063 ±11.646 T_(1/2) (hr) 0.992 ± 0.228 MRT_(last)(hr) 0.957 ± 0.269

FIGS. 9 A, B, and C show graph of PRX-002 (+) administered to the ratsat a dose of 5 mg kg orally or 2 mg/kg intravenously. Tables 39.26 and39.27 show the detailed oral and IV PK parameters.

TABLE 39.26 Single Dose Oral PK Study of PRX-002 (+isomer) at 5 mg/kgbody weight in Male Sprague Dawley Rats Mean Plasma PK ParametersParameters PRX-002 (+isomer) Dose (mg/kg b.w.) 5 C_(max) (ng/mL) 106.727± 25.432  T_(max) (hr) 0.5 ± 0.0 AUC_(last) (hr*ng/mL) 127.924 ± 74.239 AUC_(inf)(hr*ng/mL) 151.444 ± 68.603  AUC_(% extrap)(%) 18.063 ± 11.646T_(1/2) (hr) 0.992 ± 0.228 MRT_(last) (hr) 0.957 ± 0.269

TABLE 39.27 Single Dose Intravenous Pharmacokinetic Study of PRX-002(+Isomer) at 2 mg/kg body weight in Male Sprague Dawley Rats Mean PlasmaPK Parameters Parameters PRX-002 (+isomer) Route of administration IVDose (mg/kg b.w.) 2 C_(max) (ng/mL) 234.12 ± 37.91 C₀ (ng/mL) 291.216 ±61.772 T_(max)(hr) 0.08 ± 0.0 AUC_(last) (hr*ng/mL) 249.661 ± 15.19 AUC_(inf)(hr*ng/mL)  267.82 ± 23.486 AUC_(extrap)(%)  6.639 ± 2.427 Vss(L/kg) 10.07 ± 0.51 CL (mL/min/kg) 125.08 ± 10.58 T_(1/2) (hr)  1.082 ±0.152 MRT_(last) (hr)  1.05 ± 0.071

FIGS. 10 A, B, and C show graph of PRX-002 (−) administered to the ratsat a dose of 5 mg kg orally or 2 mg/kg intravenously. Tables 39.28 and39.29 show the detailed oral/IV PK parameters.

TABLE 39.28 Single Dose Oral Pharmacokinetic Study of PRX-002 (−Isomer)at 5 mg/kg body weight in Male Sprague Dawley Rats Mean Plasma PKParameters Parameters PRX-002 (−isomer) Dose (mg/kg b.w.) 5 C_(max)(ng/mL) 231.87 ± 43.45  T_(max) (hr)  0.5 ± 0.433 AUC_(last) (hr*ng/mL)419.097 ± 56.744  AUC_(inf)(hr*ng/mL) 464.727 ± 51.635 AUC_(% extrap)(%) 9.856 ± 5.812 T_(1/2) (hr) 1.112 ± 0.235 MRT_(last)(hr) 1.321 ± 0.135

TABLE 39.29 Single Dose Intravenous Pharmacokinetic Study of PRX-002(−isomer) at 2 mg/kg body weight in Male Sprague Dawley Rats Mean PlasmaPK Parameters Parameters PKX-002 (−isomer) Route of administration IVDose (mg/kg b.w.) 2 C_(max) (ng/mL) 143.117 ± 14.745 C0 (ng/mL) 199.942± 15.654 T_(max) (hr)  0.08 ± 0.00 AUC_(last) (h*ng/mL) 174.92 ± 27.20AUC_(inf)(h*ng/mL) 195.559 ± 22.32  AUC_(extrap)(%) 10.853 ± 4.23  Vss(L/kg) 18.39 ± 4.50 CL (mL/min/kg) 172.018 ± 20.611 T_(1/2) (h)  1.343 ±0.239 MRT_(last) (h)  1.248 ± 0.036

The plasma concentrations of fencamfamine were measured by LC-MS/MS overtime. TABLE 39.30 and FIGS. 1-10 demonstrate the different PK curvesachieved by the different fencamfamine prodrugs as compared withunconjugated forms and the specific pharmacokinetic parameter data ispresented in the Tables above and noted figures. The release offencamfamine from the prodrugs varied depending on the chain length ofthe fatty acid linkers attached to fencamfamine. Changes in the amountof fencamfamine released from the prodrugs was measured by the areaunder the curve and compared to unconjugated fencamfamine.

Various prodrug compositions unexpectedly provided an amount sufficientto provide an extended T_(max) when compared to unconjugatedfencamfamine when administered at equimolar doses. The prodrugcomposition showed an extended or controlled release profile as measuredby plasma concentrations of released fencamfamine when compared tounconjugated fencamfamine when administered orally at equimolar doses.However, not all of the compounds displayed all or similar suchproperties.

In some embodiments, the plasma concentration of fencamfamine releasedfrom the prodrug increased more slowly and over a longer period of timeafter oral administration, resulting in a delay in peak plasmaconcentration of released fencamfamine and in a longer duration ofaction when compared to unconjugated fencamfamine.

In addition, as shown by some of the embodiments above, the form of theisomer would also alter the pharmacokinetic profile in unexpected ways.

Thus, the type of blocking moiety associated with the drug (e.g., fattyacid or amino acid, etc.), and the particular isomer of fencamfamineused each resulted in varied properties and for the provision of thedrug in question.

A summary of the Oral and IV in vivo data in MSD rats for the variouscompounds is shown below in Table 39.30, which also demonstrates thatalternative candidate prodrugs did not have the desired properties orhad different properties. Unless otherwise specified all prodrugs weretested with a dose of 5 mg/kg orally and 2 mg/kg IV [equivalent toPRX-002 (−)]. The formulation and administration procedure is asdescribed in the beginning of the PK section.

TABLE 39.30 MEAN PLASMA PK PARAMETERS IN SPRAGUE DAWLEY RATS Oral PKParameters IV PK Parameters (5 mg/kg) (2 mg/kg) C_(max) (ng/mL) AUC(h*ng/mL) T_(max) (h) C_(max) (ng/mL) Compound Parent Prodrug ParentProdrug Parent Prodrug Parent PRX-002 232 ± 43.3 419 ± 56.7 0.5 ± 0.4143 ± 14.7 (−) isomer PRX-002 106.7 ± 25.4  127.9 ± 74.2  0.5 ± 0  234.1± 37.9  (+) isomer PRX-P1- 0 32 ± 7.5 0 42 ± 9.4 0   0.5 study not 005performed PRX-P1- 0 307 ± 49.6 0  678 ± 101.2 0 0.7 ± 0.3 study not 013performed PRX-P4-  347 ± 124.6 0  718 ± 432.2 0 0.8 ± 0.3 0 321 ± 69.2002 PRX-P4- 156.7 ± 85.3  0 296.9 ± 51.2  0 0.8 ± 0.3 0 30.8 ± 10.1  003PRX-P5- 267 ± 80.8 0 234 ± 69.4 0 0.50 ± 0   0  360 ± 104.9 002 PRX-P5- 66 ± 16.5 0 186 ± 52.6 0 1.0 ± 0  0 NC 006 PRX-P5- 144 ± 41.5 81.6 ±42.2   459 ± 188.5 477.4 ± 54.4  1.7 ± 0.6 0.8 ± 0.3 36 ± 5.0 006*PXR-P5-  39 ± 15.9 ND  69 ± 32.6 ND 0.5 ± 0  ND NP 007 PRX-P5- 59.8 ±15.0  NC 125.7 ± 22.3  NC 1.0 ± 0  NC study not 010 performed PRX-P5- 00 0 0 0 0 not 011 calculated PXR-P6- 0 721 ± 35.6 0 2433 ± 174.5 0 1.0 ±0  study not 005 performed PXR-P6- 39 ± 1.8 198 ± 19.6 45 ± 2.6 271 ±64.8 0.3 ± 0.1 0.3 ± 0.1 study not 006 performed PRX-P6- 94.6 ± 26.1 82.2 ± 30.9  227.4 ± 69.8  44.2 ± 17.1  0.75 ± 0.4  0.14 ± 0.1  studynot 011 performed IV PK Parameters (2 mg/kg) AUC (h*ng/mL) T_(max) (h)Compound Prodrug Parent Prodrug Parent Prodrug PRX-002 175 ± 27.2 0.08(−) isomer PRX-002 249.7 ± 15.2  0.08 (+) isomer PRX-P1- study notperformed 005 PRX-P1- study not performed 013 PRX-P4- 0  960 ± 201.3 0  1.5 ± 0.9 0 002 PRX-P4- 172.0 ± 62.6 14.3 ± 3.85  132.6 ± 32.5  0.08 ±0 0.08 ± 0 003 PRX-P5- 0 161 ± 42.9 0 0.08 ± 0 0 002 PRX-P5- 707.2 ±500  NC 409.6 ± 301.4 NC 0.08 ± 0 006 PRX-P5- 16425 ± 7095 125 ± 20.68061.3 ± 1764.8  1.0 ± 0 0.08 ± 0 006* PXR-P5- ND NP ND NP ND 007PRX-P5- study not performed 010 PRX-P5- not calculated 011 PXR-P6- studynot performed 005 PXR-P6- study not performed 006 PRX-P6- study notperformed 011 *PK studies performed at 15 mg/kg dose both orally andintravenously; NP: study not preformed; NC: parameter not calculated:ND: not determined.

Example 40—Oral and Intravenous Pharmacodynamic (Locomotor) ActivityExample 40A. Pharmacodynamic Response (Spontaneous Locomotor Activity)to PRX-P4-003 by Oral Administration

Male Sprague-Dawley (SD) were housed in groups of three under controlledconditions. Water and food were available ad libitum. The rats were keptfor 1 week under these conditions before behavioral test. On the day oftest rats were allowed to acclimate to the testing room for at least 30min before test compound administration. Rats were randomly assignedinto 4 groups.

Vehicle was 0.1% Tween-80 and 0.5% carboxymethylcellulose to whichrespective amount of PRX-P4-003 was added to obtain a clear solution.

Animals were p.o. administered with Veh or 3 doses of PRX-P4-003 [1, 5or 10 mg/kg equivalent dose of active compound PRX-002 (−)] at 60 minbefore spontaneous locomotor activity (sLMA) test.

The rat was placed at the center of test chamber for the 60 min sLMAvideo recording. 60 min of spontaneous locomotion activity was videorecorded and off line analyzed with Animal Behavior Video TrackingAnalysis System (Ji Liang Software Technology Co., Ltd., Shanghai,China). Total traveling distance (cm) and duration (sec) of locomotoractivity of every 15 min is presented FIGS. 11A and 11B.

As can be seen in FIGS. 11A and 11B, PRX-P4-003 showed a dose dependentincrease in sLMA when given orally.

Example 40B. Pharmacodynamic Response (Spontaneous Locomotor Activity)to PRX-P4-003 by Intravenous Administration

Male SD rats were intravenously administered with PRX-002(−) (2 mg/kg)and prodrug PRX-P4-003 [(25.8 mg/kg, equivalent to 10 mg/kg of PRX-002(−)], and vehicle just before sLMA test.

Vehicle was: 10% PEG 400 (v/v)+30% (v/v) of (50% w/v)Hydroxypropyl-ß-cyclodextrin in water+60% (v/v) sterile water forinjection (SWFI): 1 ml/kg volume.

PRX-P4-003 solution was: 25.8 mg/ml PRX-P4-003 (25.8 mg/kg: equivalentto 10 mg/ml active drug, i.v. @volume of 1 ml/kg). 42.3 mg PRX-P4-003was added to vehicle 1.639 ml, vortexed for 30 min under roomtemperature to get a uniform suspension solution, suspension solutionwas continuously stirred during dosage.

The PRX-P4-002(−) solution was: 2 mg/ml PRX-P4-002(−) (2 mg/kg,i.v.@volume of 1 ml/kg). 4.5 mg PRX-002(−) was added to 2.25 ml Vehicle,vortexed for 30 min under room temperature to get a clear solution, thesolution was continuously stirred during dosage.

Rat was placed at the center of test chamber for the 90 min sLMA videorecording. (n=3/group).

Total traveling distance (cm) and duration (sec) of locomotor activityof every 15 min is presented in FIGS. 12A and 12B. Consistent with thepresent disclosures, intravenous PRX-002 (−) significantly increasedsLMA but prodrug PRX-P4-003 showed no increase in sLMA (even at a 5times equivalent dose of active) compared to vehicle, even when givenintravenously.

As can be seen in the comparison of the results in Example 40A andExample 40B, the prodrug PRX-P4-003 resulted in higher levels of sLMAactivity when administered orally than intravenously. Indeed, while bothtraveling distance and locomotion duration increased following the oraladministration of the prodrug (FIGS. 11A and 11B), intravenousadministration resulted in practically no change (in comparison to theadministration of the active ingredient itself (PRX-002(−)). Thus, theactive drug's availability and impact upon the subject is dependent uponits route of administration of the prodrug.

While the disclosure has been illustrated and described in detail in thedrawings and foregoing description, such illustration and descriptionare to be considered illustrative or exemplary and not restrictive. Thedisclosure is not limited to the disclosed embodiments. Variations tothe disclosed embodiments can be understood and effected by thoseskilled in the art in practicing the claimed disclosure, from a study ofthe drawings, the disclosure and the appended claims.

All references cited herein are incorporated herein by reference intheir entirety. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

Unless otherwise defined, all terms (including technical and scientificterms) are to be given their ordinary and customary meaning to a personof ordinary skill in the art, and are not to be limited to a special orcustomized meaning unless expressly so defined herein. It should benoted that the use of particular terminology when describing certainfeatures or aspects of the disclosure should not be taken to imply thatthe terminology is being re-defined herein to be restricted to includeany specific characteristics of the features or aspects of thedisclosure with which that terminology is associated.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ ‘including but not limited to,’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; adjectives suchas ‘known’, ‘normal’, ‘standard’, and terms of similar meaning shouldnot be construed as limiting the item described to a given time periodor to an item available as of a given time, but instead should be readto encompass known, normal, or standard technologies that may beavailable or known now or at any time in the future; and use of termslike ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction of the disclosure, but instead as merely intended to highlightalternative or additional features that may or may not be utilized in aparticular embodiment of the disclosure. Likewise, a group of itemslinked with the conjunction ‘and’ should not be read as requiring thateach and every one of those items be present in the grouping, but rathershould be read as ‘and/or’ unless expressly stated otherwise. Similarly,a group of items linked with the conjunction ‘or’ should not be read asrequiring mutual exclusivity among that group, but rather should be readas ‘and/or’ unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article “a” or “an” does not exclude aplurality. The mere fact that certain measures are recited in mutuallydifferent dependent claims does not indicate that a combination of thesemeasures cannot be used to advantage. Any reference signs in the claimsshould not be construed as limiting the scope.

It will be further understood by those within the art that if a specificnumber of an introduced claim recitation is intended, such an intentwill be explicitly recited in the claim, and in the absence of suchrecitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould typically be interpreted to mean at least the recited number(e.g., the bare recitation of “two recitations,” without othermodifiers, typically means at least two recitations, or two or morerecitations). Furthermore, in those instances where a conventionanalogous to “at least one of A, B, and C, etc.” is used, in generalsuch a construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, and C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). In those instances where aconvention analogous to “at least one of A, B, or C, etc.” is used, ingeneral such a construction is intended in the sense one having skill inthe art would understand the convention (e.g., “a system having at leastone of A, B, or C” would include but not be limited to systems that haveA alone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term ‘about.’ Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

Furthermore, although the foregoing has been described in some detail byway of illustrations and examples for purposes of clarity andunderstanding, it is apparent to those skilled in the art that certainchanges and modifications may be practiced. Therefore, the descriptionand examples should not be construed as limiting the scope of thedisclosure to the specific embodiments and examples described herein,but rather to also cover all modification and alternatives coming withthe true scope and spirit of the disclosure.

What is claimed is:
 1. A prodrug composition comprising at least oneconjugate of N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine or any of itsstereoisomers wherein the conjugate is of the following formula (I):

wherein Y is —C(O)X; wherein: X is selected from the group consisting of—OR¹, —NHR¹, —NR¹R⁵, —O(CR²R⁶)OR³, O(CR²R⁶)SR³, and —O(CR²R⁶)NR³;wherein R¹ is independently selected from optionally substituted C₁₋₁₆alkyl, optionally substituted aryl, and optionally substitutedcycloalkyl; wherein R², R⁵, and R⁶ are independently selected fromhydrogen, optionally substituted C₁₋₆ alkyl; whererin R³ is anoptionally substituted C₁₂₋₂₆ alkanoyl.
 2. The prodrug composition ofclaim 1, wherein R¹ is selected from the group consisting of Me, Et,^(t)Bu, 5-isopropyl-2-methylphenyl, and 2-isopropyl-5-methylphenyl. 3.The prodrug composition of claim 1, wherein R² and R⁶ are independentlyselected from the group consisting of H and Me.
 4. The compound of claim1, wherein R³ is from C12 to C18 in chain length.
 5. The compound ofclaim 1, wherein X is —O(CHR²)OR³.
 6. The compound of claim 5, whereinR² is independently selected from hydrogen, optionally substituted C₁₋₆alkyl.
 7. The compound of claim 1, wherein the compound has thestructure of:


8. The compound of claim 1, wherein the compound has the structure of:


9. The prodrug composition comprising the compound of claim 1 and apharmaceutically acceptable carrier.
 10. The prodrug compositioncomprising the compound of claim 1 wherein the prodrug has an increasedplasma or blood concentration of the releasedN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine when administered orally ascompared to when it is administered intravenously and when theunconjugated drug is administered in equimolar amounts.
 11. The prodrugcomposition comprising the compound of claim 1 wherein the prodrugcomposition is in the form comprising a tablet, a capsule, elixir,emulsion solution, suspension solution, or syrup.
 12. A method fortreating cancer-related fatigue comprising administering to the subjectan effective amount of the compound of any one of claim 1 to a subjectin need thereof.
 13. The method of claim 12, wherein the prodrugcomposition provides reduced ability to abuse the drug composition whencompared to the unconjugatedN-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine.
 14. The method of claim12, wherein the subject is mammalian.
 15. The method of claim 12,wherein the subject is human.
 16. A method for treating Alzheimer'sdisease, Parkinson's disease, major depressive disorder, or attentiondeficit hyperactivity disorder comprising administering to the subjectan effective amount of the compound of claim 1 to a subject in needthereof.